ALL - Molecular Biology


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (161)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

BCR 22q11.23 ALL, CML, PHL, BCR1, D22S11, D22S662 Translocation
-BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
-BCR and Acute Lymphocytic Leukaemia
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Acute Lymphocytic Leukaemia
CD34 1q32.2 -CD34 and Acute Lymphocytic Leukaemia
PBX1 1q23.3 CAKUHED -PBX1 and Acute Lymphocytic Leukaemia
MLLT10 10p12.31 AF10 Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
-t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia
IKZF1 7p12.2 IK1, LYF1, LyF-1, CVID13, IKAROS, PPP1R92, PRO0758, ZNFN1A1, Hs.54452 -IKZF1 and Acute Lymphocytic Leukaemia
MTHFR 1p36.22 -MTHFR and Acute Lymphocytic Leukaemia
KMT2A 11q23.3 HRX, MLL, MLL1, TRX1, ALL-1, CXXC7, HTRX1, MLL1A, WDSTS Translocation
-t(4;11)(q21;q23) MLL-AFF1 in adult acute lymphoblastic leukemia
-t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia
-t(10;11) MLL-TET1 rearrangement in acute leukemias
-t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia
KITLG 12q22 SF, MGF, SCF, FPH2, FPHH, KL-1, Kitl, SHEP7 -KITLG and Acute Lymphocytic Leukaemia
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Acute Leukaemias
CD33 19q13.41 p67, SIGLEC3, SIGLEC-3 -CD33 and Acute Lymphocytic Leukaemia
CD9 12p13.31 MIC3, MRP-1, BTCC-1, DRAP-27, TSPAN29, TSPAN-29 -CD9 and Acute Lymphocytic Leukaemia
PICALM 11q14.2 LAP, CALM, CLTH Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2 Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
FIP1L1 4q12 Rhe, FIP1, hFip1 Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
CDKN2B 9p21.3 P15, MTS2, TP15, CDK4I, INK4B, p15INK4b -CDKN2B and Acute Lymphocytic Leukaemia
HLF 17q22 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
-HLF and Acute Lymphocytic Leukaemia
LMO2 11p13 TTG2, RBTN2, RHOM2, RBTNL1 -LMO2 and T-Cell Acute Lymphocytic Leukaemia
ETV6 12p13.2 TEL, THC5, TEL/ABL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
-t(12;21) in Adult Lyphocytic Leukaemia
CRLF2 Xp22.3; Yp11.3 CRL2, TSLPR, CRLF2Y -CRLF2 and Acute Lymphocytic Leukaemia
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 Translocation
-t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia
-NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL)
JAK1 1p31.3 JTK3, JAK1A, JAK1B -JAK1 and Acute Lymphocytic Leukaemia
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
CD22 19q13.12 SIGLEC2, SIGLEC-2 -CD22 and Acute Lymphocytic Leukaemia
ABL1 9q34.12 ABL, JTK7, p150, c-ABL, v-abl, c-ABL1, bcr/abl Translocation
-BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
-NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
NUP214 9q34.13 CAN, CAIN Translocation
-NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
RUNX1 21q22.12 AML1, CBFA2, EVI-1, AMLCR1, PEBP2aB, CBF2alpha, AML1-EVI-1, PEBP2alpha Translocation
-t(12;21) in Adult Lyphocytic Leukaemia
TLX1 10q24.31 TCL3, HOX11 -TLX1 and Acute Lymphocytic Leukaemia
TRG 7p14.1 TCRG, TRG@ -TRG and Acute Lymphoblastic Leukemia
TCF3 19p13.3 E2A, E47, AGM8, ITF1, VDIR, TCF-3, bHLHb21 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
SLC19A1 21q22.3 RFC, CHMD, FOLT, IFC1, REFC, RFC1, hRFC, IFC-1, RFT-1 -SLC19A1 and Acute Lymphocytic Leukaemia
ARHGEF1 19q13.2 LSC, GEF1, LBCL2, SUB1.5, P115-RHOGEF -ARHGEF1 and Acute Lymphocytic Leukaemia
TLX3 5q35.1 RNX, HOX11L2 -TLX3 and Acute Lymphocytic Leukaemia
IGK 2p12 IGK@ -IGK and Acute Lymphocytic Leukaemia
CD79A 19q13.2 IGA, MB-1 -CD79A and Acute Lymphocytic Leukaemia
STAM 10p12.33 STAM1, STAM-1 -STAM and Acute Lymphocytic Leukaemia
TPMT 6p22.3 TPMTD -TPMT and Acute Lymphocytic Leukaemia
GALE 1p36.11 SDR1E1 -GALE and Acute Lymphocytic Leukaemia
CEBPE 14q11.2 CRP1, C/EBP-epsilon -CEBPE and Acute Lymphocytic Leukaemia
EBF1 5q33.3 EBF, COE1, OLF1, O/E-1 -EBF1 and Acute Lymphocytic Leukaemia
CYP1A1 15q24.1 AHH, AHRR, CP11, CYP1, CYPIA1, P1-450, P450-C, P450DX -CYP1A1 and Acute Lymphocytic Leukaemia
ABL2 1q25.2 ARG, ABLL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
TAL1 1p33 SCL, TCL5, tal-1, bHLHa17 -TAL1 and Acute Lymphocytic Leukaemia
TRB 7q34 TCRB, TRB@ Translocation
-t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia
-t(7;19)(q35;p13) in T-cell Acute Lymphoblastic Leukemia
-TRB and Acute Lymphocytic Leukaemia
DHFR 5q14.1 DYR, DHFRP1 -DHFR and Acute Lymphocytic Leukaemia
ELL 19p13.11 MEN, ELL1, PPP1R68, C19orf17 Translocation
-ELL and Acute Lymphocytic Leukaemia
-t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia
HLA-DRB1 6p21.32 SS1, DRB1, HLA-DRB, HLA-DR1B -HLA-DRB1 and Acute Lymphocytic Leukaemia
P2RY8 Xp22.33; Yp11.3 P2Y8 -P2RY8 and Acute Lymphocytic Leukaemia
IL7R 5p13.2 ILRA, CD127, IL7RA, CDW127, IL-7R-alpha -IL7R and Acute Lymphocytic Leukaemia
CD14 5q31.3 -CD14 and Acute Lymphocytic Leukaemia
MCL1 1q21.2 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Acute Lymphocytic Leukaemia
ABCG2 4q22.1 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, MXR-1, CDw338, UAQTL1, EST157481 -ABCG2 and Acute Lymphocytic Leukaemia
JAK3 19p13.11 JAKL, LJAK, JAK-3, L-JAK, JAK3_HUMAN -JAK3 and Acute Lymphocytic Leukaemia
TYMS 18p11.32 TS, TMS, HST422 -TYMS and Acute Lymphocytic Leukaemia
JAK2 9p24.1 JTK10, THCYT3 -JAK2 mutations in Down syndrome-associated ALL
FAS 10q23.31 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Acute Lymphoblastic Leukaemia
RFC1 4p14 A1, RFC, PO-GA, RECC1, MHCBFB, RFC140 -RFC1 and Acute Lymphocytic Leukaemia
FHIT 3p14.2 FRA3B, AP3Aase -FHIT and Acute Lymphocytic Leukaemia
LMO1 11p15.4 TTG1, RBTN1, RHOM1 -LMO1 and T-Cell Leukemia-Lymphoma
LEF1 4q25 LEF-1, TCF10, TCF7L3, TCF1ALPHA -LEF1 and Acute Lymphocytic Leukaemia
CD1A 1q23.1 R4, T6, CD1, FCB6, HTA1 -CD1A and Acute Lymphocytic Leukaemia
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Acute Lymphocytic Leukaemia
BTG1 12q21.33 APRO2 -BTG1 and Acute Lymphocytic Leukaemia
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Acute Lymphocytic Leukaemia
SLCO1B1 12p12.1 LST1, HBLRR, LST-1, OATP2, OATPC, OATP-C, OATP1B1, SLC21A6 -SLCO1B1 and Acute Lymphocytic Leukaemia
FPGS 9q34.11 -FPGS and Acute Lymphocytic Leukaemia
CD79B 17q23.3 B29, IGB, AGM6 -CD79B and Acute Lymphocytic Leukaemia
RAG2 11p12 RAG-2 -RAG2 and Acute Lymphocytic Leukaemia
RAG1 11p12 RAG-1, RNF74 -RAG1 and Acute Lymphocytic Leukaemia
MTHFD1 14q23.3 MTHFC, MTHFD -MTHFD1 and Acute Lymphocytic Leukaemia
IL15 4q31.21 IL-15 -IL15 and Acute Lymphocytic Leukaemia
MLLT3 9p21.3 AF9, YEATS3 -MLLT3 and Acute Lymphocytic Leukaemia
ZNF384 12p13.31 NP, CIZ, NMP4, CAGH1, ERDA2, TNRC1, CAGH1A -ZNF384 and Acute Lymphocytic Leukaemia
HLA-DPB1 6p21.32 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Acute Lymphocytic Leukaemia
TCF7L1 2p11.2 TCF3, TCF-3 -TCF7L1 and Acute Lymphocytic Leukaemia
MTAP 9p21.3 BDMF, MSAP, DMSFH, LGMBF, DMSMFH, c86fus, HEL-249 -MTAP and Acute Lymphocytic Leukaemia
STIL 1p33 SIL, MCPH7 -STIL and Adult T-Cell Leukemia-Lymphoma
MLLT1 19p13.3 ENL, LTG19, YEATS1 -MLLT1 and Acute Lymphocytic Leukaemia
CASP8AP2 6q15 CED-4, FLASH, RIP25 -CASP8AP2 and Acute Lymphocytic Leukaemia
ABCC4 13q32.1 MRP4, MOATB, MOAT-B -ABCC4 and Acute Lymphocytic Leukaemia
HFE 6p22.2 HH, HFE1, HLA-H, MVCD7, TFQTL2 -HFE and Acute Lymphocytic Leukaemia
MEF2C 5q14.3 DEL5q14.3, C5DELq14.3 -MEF2C and Acute Lymphocytic Leukaemia
CEACAM6 19q13.2 NCA, CEAL, CD66c -CEACAM6 and Acute Lymphocytic Leukaemia
HOXA7 7p15.2 ANTP, HOX1, HOX1A, HOX1.1 -HOXA7 and Acute Lymphocytic Leukaemia
CD58 1p13.1 ag3, LFA3, LFA-3 -CD58 and Acute Lymphocytic Leukaemia
BIRC7 20q13.33 KIAP, LIVIN, MLIAP, RNF50, ML-IAP -BIRC7 and Acute Lymphocytic Leukaemia
PMS2 7p22.1 MLH4, PMSL2, HNPCC4, PMS2CL -PMS2 and Acute Lymphocytic Leukaemia
IL7 8q21.13 IL-7 -IL7 and Acute Lymphocytic Leukaemia
SLC29A1 6p21.1 ENT1 -SLC29A1 and Acute Lymphocytic Leukaemia
OLAH 10p13 SAST, AURA1, THEDC1 -OLAH and Acute Lymphocytic Leukaemia
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Acute Lymphocytic Leukaemia
IDH1 2q33.3 IDH, IDP, IDCD, IDPC, PICD, HEL-216, HEL-S-26 -IDH1 and Acute Lymphocytic Leukaemia
TAF15 17q12 Npl3, RBP56, TAF2N, TAFII68 -TAF15 and Acute Lymphocytic Leukaemia
TYK2 19p13.2 JTK1, IMD35 -TYK2 and Acute Lymphocytic Leukaemia
SLC19A2 1q24.2 TC1, THT1, TRMA, THMD1, THTR1 -SLC19A2 and Acute Lymphocytic Leukaemia
PBX3 9q33.3 -PBX3 and Acute Lymphocytic Leukaemia
CCNC 6q21 CycC -CCNC and Acute Lymphocytic Leukaemia
AFF3 2q11.2-q12 LAF4, MLLT2-like -AFF3 and Acute Lymphocytic Leukaemia
BCL2L11 2q13 BAM, BIM, BOD -BCL2L11 and Acute Lymphocytic Leukaemia
GAST 17q21.2 GAS -GAST and Acute Lymphocytic Leukaemia
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Acute Lymphocytic Leukaemia
CTLA4 2q33 CD, GSE, GRD4, ALPS5, CD152, CTLA-4, IDDM12, CELIAC3 -CTLA4 and Acute Lymphocytic Leukaemia
ABCC2 10q24.2 DJS, MRP2, cMRP, ABC30, CMOAT -ABCC2 and Acute Lymphocytic Leukaemia
NOD2 16q12.1 CD, ACUG, BLAU, IBD1, YAOS, BLAUS, NLRC2, NOD2B, CARD15, CLR16.3, PSORAS1 -NOD2 and Acute Lymphocytic Leukaemia
TFPT 19q13.42 FB1, amida, INO80F -TFPT and Acute Lymphocytic Leukaemia
PTPRG 3p21-p14 PTPG, HPTPG, RPTPG, R-PTP-GAMMA -PTPRG and Acute Lymphocytic Leukaemia
ZNF521 18q11.2 EHZF, Evi3 -ZNF521 and Acute Lymphocytic Leukaemia
CD83 6p23 BL11, HB15 -CD83 and Acute Lymphocytic Leukaemia
CD3D 11q23.3 T3D, IMD19, CD3-DELTA -CD3D and Acute Lymphocytic Leukaemia
RANBP17 5q35.1 -RANBP17 and Acute Lymphocytic Leukaemia
CD69 12p13.31 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Acute Lymphocytic Leukaemia
MIR126 9q34.3 MIRN126, mir-126, miRNA126 -MicroRNA mir-126 and Acute Lymphocytic Leukaemia
TET1 10q21.3 LCX, CXXC6, bA119F7.1 Translocation
-t(10;11) MLL-TET1 rearrangement in acute leukemias
SFPQ 1p34.3 PSF, POMP100, PPP1R140 -SFPQ and Acute Lymphocytic Leukaemia
FMR1 Xq27.3 POF, FMRP, POF1, FRAXA -FMR1 and Acute Lymphocytic Leukaemia
PRF1 10q22.1 P1, PFP, FLH2, PFN1, HPLH2 -PRF1 and Acute Lymphocytic Leukaemia
GSTO1 10q25.1 P28, SPG-R, GSTO 1-1, GSTTLp28, HEL-S-21 -GSTO1 and Acute Lymphocytic Leukaemia
NNAT 20q11.23 Peg5 -NNAT and Acute Lymphocytic Leukaemia
IL2RB 22q12.3 CD122, IMD63, IL15RB, P70-75 -IL2RB and Acute Lymphocytic Leukaemia
CHFR 12q24.33 RNF116, RNF196 -CHFR and Acute Lymphocytic Leukaemia
HCK 20q11.21 JTK9, p59Hck, p61Hck -HCK and Acute Lymphocytic Leukaemia
PTER 10p13 HPHRP, RPR-1 -PTER and Acute Lymphocytic Leukaemia
CD55 1q32.2 CR, TC, DAF, CROM, CHAPLE -CD55 and Acute Lymphocytic Leukaemia
HOXC6 12q13.13 CP25, HOX3, HOX3C, HHO.C8 -HOXC6 and Acute Lymphocytic Leukaemia
CD70 19p13.3 CD27L, CD27-L, CD27LG, TNFSF7, TNLG8A -CD70 and Acute Lymphocytic Leukaemia
MLLT6 17q12 AF17 -MLLT6 and Acute Lymphocytic Leukaemia
LRRC3B 3p24.1 LRP15 -LRRC3B and Acute Lymphocytic Leukaemia
CDK2AP1 12q24.31 DOC1, ST19, DORC1, doc-1, p12DOC-1 -CDK2AP1 and Acute Lymphocytic Leukaemia
B2M 15q21.1 IMD43 -B2M and Acute Lymphocytic Leukaemia
TTL 2q13 -TTL and Acute Lymphocytic Leukaemia
TFRC 3q29 T9, TR, TFR, p90, CD71, TFR1, TRFR, IMD46 -TFRC and Acute Lymphocytic Leukaemia
MNX1 7q36.3 HB9, HLXB9, SCRA1, HOXHB9 -MNX1 and Acute Lymphocytic Leukaemia
BLNK 10q24.1 bca, AGM4, BASH, LY57, SLP65, BLNK-S, SLP-65 -BLNK and Acute Lymphocytic Leukaemia
CTNND1 11q12.1 CAS, p120, CTNND, P120CAS, P120CTN, p120(CAS), p120(CTN) -CTNND1 and Acute Lymphocytic Leukaemia
RASSF10 11p15.3 -RASSF10 and Acute Lymphocytic Leukaemia
PECAM1 17q23.3 CD31, PECA1, GPIIA', PECAM-1, endoCAM, CD31/EndoCAM -PECAM1 and Acute Lymphocytic Leukaemia
ARHGEF12 11q23.3 LARG, PRO2792 -ARHGEF12 and Acute Lymphocytic Leukaemia
NR3C2 4q31.23 MR, MCR, MLR, NR3C2VIT -NR3C2 and Acute Lymphocytic Leukaemia
FCRL4 1q23.1 FCRH4, IGFP2, IRTA1, CD307d -FCRL4 and Acute Lymphocytic Leukaemia
RASSF6 4q13.3 -RASSF6 and Acute Lymphocytic Leukaemia
ITGB2 21q22.3 LAD, CD18, MF17, MFI7, LCAMB, LFA-1, MAC-1 -ITGB2 and Acute Lymphocytic Leukaemia
ARHGAP26 5q31.3 GRAF, GRAF1, OPHN1L, OPHN1L1 -ARHGAP26 and Acute Lymphocytic Leukaemia
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Acute Lymphocytic Leukaemia
SNRPE 1q32.1 SME, Sm-E, HYPT11, snRNP-E -SNRPE and Acute Lymphocytic Leukaemia
ADIPOQ 3q27 ACDC, ADPN, APM1, APM-1, GBP28, ACRP30, ADIPQTL1 -ADIPOQ and Acute Lymphocytic Leukaemia
ACKR3 2q37.3 RDC1, CXCR7, RDC-1, CMKOR1, CXC-R7, CXCR-7, GPR159 -ACKR3 and Acute Lymphocytic Leukaemia
DOK2 8p21.3 p56DOK, p56dok-2 -DOK2 and Acute Lymphocytic Leukaemia
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Acute Lymphocytic Leukaemia
TPD52L1 6q22.31 D53 -TPD52L1 and Acute Lymphocytic Leukaemia
FCGR2B 1q23.3 CD32, FCG2, CD32B, FCGR2, IGFR2, FCGR2C, FcRII-c -FCGR2B and Acute Lymphocytic Leukaemia
PRTN3 19p13.3 MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA -PRTN3 and Acute Lymphocytic Leukaemia
SOCS1 16p13.13 JAB, CIS1, SSI1, TIP3, CISH1, SSI-1, SOCS-1 -SOCS1 and Acute Lymphocytic Leukaemia
DPH1 17p13.3 DPH2L, OVCA1, DEDSSH, DPH2L1 -DPH1 and Acute Lymphocytic Leukaemia
IFNA17 9p21.3 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Acute Lymphocytic Leukaemia
SERPINC1 1q25.1 AT3, AT3D, ATIII, THPH7, ATIII-R2, ATIII-T1, ATIII-T2 -SERPINC1 and Acute Lymphocytic Leukaemia
IFNA2 9p21.3 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Acute Lymphocytic Leukaemia
IFNA7 9p21.3 IFNA-J, IFN-alphaJ -IFNA7 and Acute Lymphocytic Leukaemia
TNFRSF8 1p36.22 CD30, Ki-1, D1S166E -TNFRSF8 and Acute Lymphocytic Leukaemia
LYL1 19p13.13 bHLHa18 Translocation
-t(7;19)(q35;p13) in T-cell Acute Lymphoblastic Leukemia
BCL2 18q21.33 Bcl-2, PPP1R50 Translocation
-t(14;18)(q32;q21) in Acute Lymphoblastic Leukaemia
AFF1 4q21.3-q22.1 AF4, PBM1, MLLT2 Translocation
-t(4;11)(q21;q23) MLL-AFF1 in adult acute lymphoblastic leukemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Latest Publications

Tian L, Shao Y, Nance S, et al.
Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.
Nat Commun. 2019; 10(1):2789 [PubMed] Free Access to Full Article Related Publications
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.

Guo W, Liu S, Liu HY, et al.
[β-arrestin 1 Promotes Senescence of Acute Lymphoblastic Leukemia Jurkat Cells].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(3):777-784 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of β-arrestin1 gene on senescence of T-ALL cells and its possible mechanism.
METHODS: The bone marrow specimens of T-ALL patients and controls were collected, the expression of β-arrestin1 and β-arrestin1 in the T-ALL patients was detected by RT-PCR and Western blot, respectively, and the relation of β-arrestin1 expression with the clinical pathologic characteristics and the prognosis of T-ALL patients was analyzed statistically. The stable Jurkat cell line with knocked down or overexpressed β-arrestin1 was constructed, the CCK method was used to detect the Jurkat cell number, the β-gal staining was used to analyze the effect of β-arrestin1 on senescence of Jurkat cells, the cross analysis of RNA-Seg data and KEGG data was performed for screening the possible signaling pathway, and Western blot was performed for varifying the key sites of signaling pathway.
RESULTS: The β-arrestin1 expression in specimens of T-ALL patients decreased (P<0.01), moreover the β-arrestin1 expression negatively related with peripheral blood cell number (r=-0.601), the blasts in peripheral blood (r=-0.516) and extramedullary infiltration (r=-0.359), while positively related with the response to chemotherapy (r=0.393). The detection of stable Jurkat cell line with knocked-down and overexpressed β-arrestin1 found that the β-arrestin 1 could decrease the Jurkat cell number and accelarate the senescence of Jurkat cells (P<0.05). The cross analysis of RNA-Seg data and KEGG data showed that the senescence of T-ALL cells may be regulated via RAS-P16-PRb-E2F1 by β-arrestin 1. Western bolt confirmed that β-arrestin1 promoted the expression of Ras and p16, and decreased the expression of pRB and E2F1 (P<0.05).
CONCLUSIONS: β-arrestin1 accelerates the senescence of Jurkat cells via Ras-p16-pRb-E2F1, and delays the progression in T-ALL, which may provide a new hypothesis for the pathogenesis of T-ALL.

Han Q, Gu Y, Gao YQ, et al.
[Characteristics and Clinical Significance of RAG1 Expression in Adult B-Cell Acute Lymphoblastic Leukemia].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(3):735-740 [PubMed] Related Publications
OBJECTIVE: RAG1 plays important roles in lymphopoiesis and immune system, its dysfunction may result in the malignancies of hemopoietic system. The aim of this study was to investigate the characteristics of RAG1 expression in adult B-cell acute lymphoblastic leukemia (B-ALL), and to analyze the clinical significances.
METHODS: Quantitative PCR (q-PCR) was performed to evaluate the expression of RAG1 in 104 newly diagnosed, 22 relapsed adult B-ALL patients and 30 normal controls, the clinical significances of RAG1 expression were analyzed.
RESULTS: Compared with normal controls, newly diagnosed and relapsed adult B-ALL patients showed higher RAG1 expression level (3.94 vs 1.23) (P<0.01), (5.86 vs 1.23) (P<0.01). The analysis of paired simples from 6 cases of newly diagnosed and relapsed B-ALL showed that the expression level of RAG1 at relapse was significantly higher than that at new diagnosis (13.65 vs 2.31) (P<0.01). The RAG1 expression level in IK6 positive patients was higher than that in IK6 negative patients (5.30 vs 2.11) (P<0.05). The ratio of patients with LDH>1 000 U/L in RAG1 high expression group was higher than that in RAG1 low expression group (42.2% vs 20.5%) (P<0.05).
CONCLUSION: RAG1 up-regulation may play an important role in the development of adult B-ALL especially when relapsed, which may also take part in the formation of Ik6. Monitoring RAG1 expression may provide a new method to evaluate the prognosis of adult B-ALL patients.

Liu KQ, Gong XY, Zhao XL, et al.
[Clinical Features and Therapeutic Efficacy in Adult Acute Lymphoblastic Leukemia with t (1; 19) (E2A-PBX1)].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(3):637-640 [PubMed] Related Publications
OBJECTIVE: To explore the clinical features and therapeutic efficacy in adult ALL patients with t (1; 19) (E2A-PBX1).
METHODS: The clinic data of 19 adult ALL patients with t (1; 19) (E2A-PBX1) in our hospital from Nov. 22, 2010 to Apr. 4, 2018 were collected. The clinical features,complete remission (CR) rate, overall survival (OS) rate and relapse-free survival (RFS) rate of patients received chemotherapy and chemotherapy+HSCT were analyzed.
RESULTS: In all the 19 patients, the median age was 24 (14-66), median WBC count was 16.47×109 (1.8-170.34)/L, median Hb level was 98 (65-176) g/L, median Plt count was 50 (15-254)×109/L. Pre B-ALL were 17 cases (89.5%), and common B-ALL were 2 cases (10.5%). Patients received the induction therapy, the overall CR rate was 94.7%, one course CR rate was 94.7%, 4 year OS rate was 47.1% and RFS rate was 43.3%. The OS rate and RFS rate of patients received transplantation were slightly higher than those of patients not received transplantation (OS: 62.5% vs 36.7%) (P=0.188);RFS (62.5% vs 38.9%) (P=0.166).
CONCLUSION: Most adult ALL patients with t (1; 19) (E2A-PBX1) is Pre B-ALL by Immunophenotyping, as compared with the pediatric patients, the therapeutic efficacy for adult patients with t (1; 19) (E2A-PBX1) is worsen, therefore, stem cell transplantation is still acquired for better long term survival.

Li F, Wang J, Liu A, et al.
Prolonged lumbosacral pain as the initial presentation in acute lymphoblastic leukemia in an adult: A case report.
Medicine (Baltimore). 2019; 98(24):e15912 [PubMed] Free Access to Full Article Related Publications
RATIONALE: The differential diagnosis of conditions manifesting as bone and joint pain is complex. Although many individuals with acute leukemia experience bone pain, lumbosacral pain as an early feature of acute lymphoblastic leukemia (ALL) is rare.
PATIENT CONCERNS: Here we report a case of an adult who presented with a 7-month history of persistent lumbosacral pain which had become more severe during the previous month.
DIAGNOSES: Prior to referral, his full blood count revealed no abnormalities, and a computerized tomography scan revealed mild bone hyperplasia of his lumbar vertebrae, with disc herniations of L3-S1. His blood biochemistry and urinary test results had been normal. After referral to our clinic, tests of the morphology, immunology, cytogenetics, and molecular biology of his bone marrow led to a diagnosis of MLL-AF4 fusion positive B-cell ALL.
INTERVENTIONS: Prior to his referral, he had been treated with painkillers by local doctors. The painkillers initially provided pain relief, but their effect wore off over time. After diagnosis, he was started on an adult ALL chemotherapy protocol.
OUTCOMES: His symptoms resolved within a week of starting chemotherapy. At his most recent assessment, 10 months after diagnosis, he was on maintenance chemotherapy and in remission.
LESSONS: This case illustrates that prolonged lumbosacral pain may be a symptom of a life-threatening condition, rather than only attributable to chronic inflammation or disk herniations. Therefore, clinicians need to pay attention to subtle differences in the clinical presentation of patients with lumbosacral pain.

Kampen KR, Fancello L, Girardi T, et al.
Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells.
Nat Commun. 2019; 10(1):2542 [PubMed] Free Access to Full Article Related Publications
Somatic ribosomal protein mutations have recently been described in cancer, yet their impact on cellular transcription and translation remains poorly understood. Here, we integrate mRNA sequencing, ribosome footprinting, polysomal RNA sequencing and mass spectrometry datasets from a mouse lymphoid cell model to characterize the T-cell acute lymphoblastic leukemia (T-ALL) associated ribosomal RPL10 R98S mutation. Surprisingly, RPL10 R98S induces changes in protein levels primarily through transcriptional rather than translation efficiency changes. Phosphoserine phosphatase (PSPH), encoding a key serine biosynthesis enzyme, was the only gene with elevated transcription and translation leading to protein overexpression. PSPH upregulation is a general phenomenon in T-ALL patient samples, associated with elevated serine and glycine levels in xenograft mice. Reduction of PSPH expression suppresses proliferation of T-ALL cell lines and their capacity to expand in mice. We identify ribosomal mutation driven induction of serine biosynthesis and provide evidence supporting dependence of T-ALL cells on PSPH.

Kimura S
[Genetic and epigenetic landscape of pediatric T-cell acute lymphoblastic leukemia].
Rinsho Ketsueki. 2019; 60(5):459-467 [PubMed] Related Publications
Recent development of massive parallel-sequencing technology has revealed the genetic basis of pediatric T-cell acute lymphoblastic leukemia (T-ALL). However, epigenetic profiles of T-ALL, such as DNA methylation, have not been well characterized. To describe the epigenetic landscape of T-ALL, we investigated DNA methylation profiles of 79 cases with pediatric T-ALL by using the EPIC methylation array, which allowed us to perform more profound analyses, including the OpenSea region. Moreover, we conducted combined analyses of methylation data using our previous expression and mutation data. Based on DNA methylation profiles, pediatric T-ALL was clustered into four distinct subtypes, which exhibited remarkable association with genetic signatures and expression features, as well as profiles of normal T-cell development. Furthermore, our study revealed the importance of methylation status at binding sites of polycomb-repressive complex components and transcription factors, such as SPI1, in the classification of pediatric T-ALL based on DNA methylation status. These results might be helpful in the development of new therapeutic strategies for pediatric T-ALL.

Conant JL, Czuchlewski DR
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies.
Int J Lab Hematol. 2019; 41 Suppl 1:126-130 [PubMed] Related Publications
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like ALL or Ph-like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B-ALL with t(9;22)(q34.1;q11.2) BCR-ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%-20% of pediatric cases and 20%-30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR-ABL1-like ALL, particularly in adults and pediatric patients with high-risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR-ABL1-like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.

Bai J, Li L, Li Y, et al.
Methylation of the promoter region of the MTRR gene in childhood acute lymphoblastic leukemia.
Oncol Rep. 2019; 41(6):3488-3498 [PubMed] Related Publications
Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5‑methyltetrahydrofolate‑homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT‑qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age‑ and sex‑matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI‑TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low‑risk group had a higher methylation rate of CpG_6 compared to the medium‑risk group. However, the medium‑risk group had a higher CpG_46.47 methylation rate compared to the low‑risk group. The methylation rates of CpG_26 and CpG_46.47 in the high‑risk group were higher than these rates in the low‑risk group, while the CpG_42.23.44 methylation rate was lower in the high‑risk group than in the low‑risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL‑H (high) group (≥50x109/l) were lower than these in the ALL‑NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.

Ayón-Pérez MF, Pimentel-Gutiérrez HJ, Durán-Avelar MJ, et al.
IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico.
Cytogenet Genome Res. 2019; 158(1):10-16 [PubMed] Related Publications
The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.

Sharma ND, Nickl CK, Kang H, et al.
Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.
Cancer Sci. 2019; 110(6):1931-1946 [PubMed] Free Access to Full Article Related Publications
Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.

Wang X, Yang J, Guo G, et al.
Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.
Mol Cancer. 2019; 18(1):84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Schittenhelm MM, Walter B, Tsintari V, et al.
Alternative splicing of the tumor suppressor ASPP2 results in a stress-inducible, oncogenic isoform prevalent in acute leukemia.
EBioMedicine. 2019; 42:340-351 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Apoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. TP53 mutations found in cancers disrupt ASPP2 binding, arguing for an important role of ASPP2 in TP53-mediated tumor suppression. We now identify an oncogenic splicing variant, ASPP2κ, with high prevalence in acute leukemia.
METHODS: An mRNA screen to detect ASPP2 splicing variants was performed and ASPP2κ was validated using isoform-specific PCR approaches. Translation into a genuine protein isoform was evaluated after establishing epitope-specific antibodies. For functional studies cell models with forced expression of ASPP2κ or isoform-specific ASPP2κ-interference were created to evaluate proliferative, apoptotic and oncogenic characteristics of ASPP2κ.
FINDINGS: Exon skipping generates a premature stop codon, leading to a truncated C-terminus, omitting the TP53-binding sites. ASPP2κ translates into a dominant-negative protein variant impairing TP53-dependent induction of apoptosis. ASPP2κ is expressed in CD34+ leukemic progenitor cells and functional studies argue for a role in early oncogenesis, resulting in perturbed proliferation and impaired induction of apoptosis, mitotic failure and chromosomal instability (CIN) - similar to TP53 mutations. Importantly, as expression of ASPP2κ is stress-inducible it defines a novel class of dynamic oncogenes not represented by genomic mutations.
INTERPRETATION: Our data demonstrates that ASPP2κ plays a distinctive role as an antiapoptotic regulator of the TP53 checkpoint, rendering cells to a more aggressive phenotype as evidenced by proliferation and apoptosis rates - and ASPP2κ expression results in acquisition of genomic mutations, a first initiating step in leukemogenesis. We provide proof-of-concept to establish ASPP2κ as a clinically relevant biomarker and a target for molecule-defined therapy. FUND: Unrestricted grant support from the Wilhelm Sander Foundation for Cancer Research, the IZKF Program of the Medical Faculty Tübingen, the Brigitte Schlieben-Lange Program and the Margarete von Wrangell Program of the State Ministry Baden-Wuerttemberg for Science, Research and Arts and the Athene Program of the excellence initiative of the Eberhard-Karls University, Tübingen.

Fazio G, Massa V, Grioni A, et al.
First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia.
J Clin Pathol. 2019; 72(8):558-561 [PubMed] Related Publications
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes

Yang M, Vesterlund M, Siavelis I, et al.
Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.
Nat Commun. 2019; 10(1):1519 [PubMed] Free Access to Full Article Related Publications
Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.

Zhang R, Deng Q, Jiang YY, et al.
Effect and changes in PD‑1 expression of CD19 CAR‑T cells from T cells highly expressing PD‑1 combined with reduced‑dose PD‑1 inhibitor.
Oncol Rep. 2019; 41(6):3455-3463 [PubMed] Related Publications
CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B‑cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non‑Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death‑1/programmed death‑ligand 1 (PD‑1/PD‑L1) inhibitors in numerous malignancies, but the immune‑associated adverse events of PD‑1/PD‑L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR‑T cells with a reduced dose of PD‑1 inhibitor. This method is expected to overcome the side-effects of PD‑1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD‑1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR‑T cells. An interesting finding of the present study was that the number of PD‑1‑positive cells CAR‑T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co‑culture time of CD19 CAR‑T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR‑T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR‑T cells on B‑cell lymphoma is unsatisfactory compared with B‑cell leukemia. The synergistic effect of a reduced‑dose PD‑1 inhibitor combined with CD19 CAR‑T cells from T cells highly expressing PD‑1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR‑T cells and the level of interleukin‑6 were higher compared with those in the CAR‑T cell group. In conclusion, a reduced dose of a PD‑1 inhibitor combined with CD19 CAR‑T cells appears to be a promising treatment option for relapsed/refractory B‑NHL exhibiting high PD‑1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD‑1 inhibitors.

Brattås MK, Reikvam H, Tvedt THA, Bruserud Ø
Dasatinib as an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.
Expert Opin Investig Drugs. 2019; 28(5):411-420 [PubMed] Related Publications
INTRODUCTION: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1

Zhu X, Liu Y, Chen G, et al.
Association between NAT2 polymorphisms and acute leukemia risk: A meta-analysis.
Medicine (Baltimore). 2019; 98(12):e14942 [PubMed] Related Publications
BACKGROUND: N-acetyl-transferase 2 (NAT2) polymorphisms have been demonstrated to be associated with acute leukemia (AL); however, the results remain controversial. The present meta-analysis was performed to provide more precise results.
METHODS: Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were used to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 polymorphisms and AL risk.
RESULTS: Increased risk was found under both heterozygous (OR 1.24, 95% CI 1.02-1.51) and recessive model (OR 1.28, 95% CI 1.06-1.55) for rs1801280. The slow acetylator phenotype (OR 1.22, 95% CI 1.07-1.40) also increased AL risk. Subgroup analysis demonstrated that rs1801280 increased AL risk under the recessive model (OR 1.14, 95% CI 0.93-1.41) in Caucasian population and the co-dominant (OR 1.77, 95% CI 1.40-2.23), homozygous (OR 3.06, 95% CI 1.88-4.99), dominant (OR 2.22, 95% CI 1.56-3.17), recessive model (OR 2.06, 95% CI 1.35-3.16) in the Mixed populations. Association between rs1799929 and decreased AL risk was found in the co-dominant (OR 0.82, 95% CI 0.70-0.97), homozygous (OR 0.65, 95% CI 0.46-0.93), heterozygous (OR 0.71, 95% CI 0.51-1.00), and the recessive model (OR 0.68, 95% CI 0.49-0.94) in the Caucasian group. As for rs1799931, the same effects were found in the co-dominant (OR 0.68, 95% CI 0.49-0.94) and the dominant model (OR 0.68, 95% CI 0.48-0.97) in the mixed group.
CONCLUSION: rs1801280 and the slow acetylator phenotype are risk factors for AL.

Rashed WM, Hammad AM, Saad AM, Shohdy KS
MicroRNA as a diagnostic biomarker in childhood acute lymphoblastic leukemia; systematic review, meta-analysis and recommendations.
Crit Rev Oncol Hematol. 2019; 136:70-78 [PubMed] Related Publications
Several studies detected abnormal mi-RNAs expression levels in childhood Acute Lymphoblastic Leukemia (ALL) with potential diagnostic value. We conducted a systematic search on certain microRNAs in childhood ALL. We included 17 studies with a total of 928 ALL children and 307 controls. Ten studies provided miRNAs expression levels and seven provided frequency data. Sensitivity and specificity of a single miRNA ranged from 46.55% to 100% and from 71.8% to 100%, respectively. The highest diagnostic odds ratio (DOR) was for the diagnostic panel (miR-128a and miR-223) reaching 546 [95% CI: 73.768-4041.282]. Also, miR-128a, miR-128b, miR-223, let-7b, miR-155 and miR-24 can be used as diagnostic discriminatory biomarkers between ALL and AML. Further large cohort studies are needed to confirm our results.

Mehrvar N, Akbari ME, Rezvany MR, et al.
ATP-Binding Cassette transporters' gene expression in pediatric patients with acute leukemia; a comprehensive analysis of published reports through PubMed search engine.
Cell Mol Biol (Noisy-le-grand). 2019; 65(2):7-13 [PubMed] Related Publications
Multidrug resistance based on ABC transporters' gene expression is one of the most important health challenges through chemotherapy of patients. This resistance can cause relapse or treatment failure. The goal of this conducted study was to evaluate the results of published reports which considered ABC transporters' gene expression in pediatric patients with acute leukemia. PubMed as a free search engine was chosen. The following Mesh terms were used as: "ATP-binding cassette transporters" OR "ABC-transporters*" AND "gene expression*" AND "leukemia" OR "ALL" OR "AML" OR "acute leukemia*". Age was set as an additional filter with the age range of birth to 18 years old. Initial screening was performed according to inclusion and exclusion criteria and the quality of the selected papers was assessed. Papers categorized into three sections as: pediatric patients with ALL (6 papers from 1998-2015); pediatric patients with AML (3 papers from 1992-2011) and pediatric patients with ALL and AML (7 papers from 1992-2014). Totally 1118 patients enrolled in the searched studies (ALL and AML: 488; ALL: 405; AML: 225). The common method for evaluating gene expression of ABC transporters was RT-PCR. More than 50% of the papers showed the influence of ABC transporters' gene expression on prognosis and treatment failures of patients. Despite controversial results, the gathered information in the current report serves as a comprehensive referential resource, which can be beneficial for future planning around this title, especially in developing countries.

Hsu PC, Pei JS, Chen CC, et al.
Association of
Anticancer Res. 2019; 39(3):1185-1190 [PubMed] Related Publications
BACKGROUND/AIM: The association of matrix metalloproteinase-2 (MMP-2) genotypes with adult leukemia has been reported only once, but never for childhood leukemia. This study aimed to determine the role of MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes in childhood leukemia risk.
MATERIALS AND METHODS: This case-control study included 266 patients and 266 age- and gender-matched healthy controls. The polymorphic sites of MMP-2 were genotyped by typical polymerase chain reaction-restriction fragment length polymorphism.
RESULTS: The CC, CT and TT of rs243865 genotype were 75.2, 23.7 and 1.1% in the case group and 69.2, 28.9 and 1.9% in the control group, respectively. The CT and TT genotypes caused a 0.75- and 0.55-fold increase in the risk of childhood leukemia, respectively. There was no differential distribution of rs2285053 genotypes. Allelic frequency analysis showed that the T allele of MMP-2 promoter -1306 and -735 conferred lower susceptibility than the C allele.
CONCLUSION: The MMP-2 promoter genotypes play a minor role in determining personal susceptibility to childhood leukemia among the Taiwanese.

Richter A, Roolf C, Hamed M, et al.
Combined Casein Kinase II inhibition and epigenetic modulation in acute B-lymphoblastic leukemia.
BMC Cancer. 2019; 19(1):202 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways.
METHODS: Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice.
RESULTS: CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous.
CONCLUSIONS: We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.

Sabarimurugan S, Madurantakam Royam M, Kumarasamy C, et al.
Prognostic miRNA classifiers in t cell acute lymphoblastic leukemia: Study protocol for a systematic review and meta-analysis of observational clinical studies.
Medicine (Baltimore). 2019; 98(9):e14569 [PubMed] Related Publications
BACKGROUND: The prognostic value of microRNA (miRNA) expression in T-cell acute lymphoblastic leukemia (T-ALL) has generated significant research interest in recent years. However, most diagnostic and prognostic studies with regards to miRNA expression have been focused on combined B cell and T cell lymphoblastic leukemia. There are very few studies reporting the prognostic effects of miRNA expression on T-ALL. Therefore, a pioneer systematic review and meta-analysis was proposed to explore the possibilities of miRNAs as viable prognostic markers in T-ALL. This study is intended to be useful as a guideline for future research into drug evaluation and targeting miRNA as a biomarker for the treatment and prognosis of T-ALL.
METHODS: The systematic review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The study search will be conducted by using Cochrane, EMBASE, Medline, Science Direct, and SCOPUS bibliographic databases. The reference lists of included studies will be manually searched to further bolster the search results. A combination of keywords will be used to search the databases.
DISCUSSION: To explore the effect of miRNA on prognosis, forest plots will be generated to assess pooled HR and 95% CI. Upregulation, downregulation, and deregulation of specific miRNAs will be individually noted and used to extrapolate patient prognosis when associated with risk factors involved in T-ALL. Subgroup analysis will be carried out to analyze the effect of deregulation of miRNA expression on patient prognosis. A fixed or random-effects model of meta-analysis will be used depending upon between-study heterogeneity. This systematic review and meta-analysis will identify and synthesize evidence to determine the prognosis of miRNA in T-ALL and suggest the possible miRNA from meta-analysis results to predict as a biomarker for further detection and treatment of T-ALL.

Al-Aamri HM, Ku H, Irving HR, et al.
Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia.
BMC Cancer. 2019; 19(1):179 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Daunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods.
METHODS: Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 h treatment with daunorubicin chemotherapy and 4, 12 and 24 h recovery periods. Cell viability was measured via MTT (3-(4,5-dimethylthiazol-2-yl)-2-5 diphenyltetrazolium bromide) assay, reactive oxygen species (ROS) production by flow cytometry, double stranded DNA breaks by detecting γH2AX levels while stages of the cell cycle were detected following propidium iodide staining and flow cytometry. Western blotting was used to detect specific proteins while RNA was extracted from all cell lines and converted to cDNA to sequence Ataxia-telangiectasia mutated (ATM).
RESULTS: Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by γH2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in ATM as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells.
CONCLUSIONS: The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 that may be correlated to increased expression of SOD2 and lower ROS production.

Bhat A, Shah R, Bhat GR, et al.
Association of ARID5B and IKZF1 Variants with Leukemia from Northern India.
Genet Test Mol Biomarkers. 2019; 23(3):176-179 [PubMed] Related Publications
BACKGROUND: Leukemia is a heterogeneous disorder, characterized by elevated proliferation of white blood cells. Various genetic studies have assessed the contributory roles of several single nucleotide polymorphisms with the development of leukemia. The role of genetic variation in the ARID5B and IKZF1 genes has previously been identified in various population groups; however, the role of these variants in the north Indian populations of Jammu and Kashmir is unknown.
AIM: In this study, we explored the association of the newly identified genetic variants, rs10740055 of ARID5B and rs6964823 of IKZF1, with leukemic patients from Jammu and Kashmir of northern India.
METHODS: The variants were genotyped using TaqMan allele discrimination assays for 616 individuals (210 leukemic cases and 406 healthy controls). The association of each SNP with the disease was evaluated using logistic regression.
RESULTS: It was observed that the variants rs6964823 (IKZF1) and rs10740055 (ARID5B) showed significant associations with odds ratio (OR) and p-values of 1.5 (1.0-2.3 at 95% confidence interval [CI]) and 0.04; and 2.5 (1.5-4.1 at 95% CI) and 0.0002, respectively. We also evaluated the cumulative effect for both the variants by combining the risk genotypes and obtained and OR of 4.9.
DISCUSSION: It was found that the variants rs10740055 of ARID5B and rs6964823 of IKZF1 act individually and additively as risk factors in the development of leukemia in the populations of Jammu and Kashmir in Northern India.

Dawidowska M, Jaksik R, Drobna M, et al.
Comprehensive Investigation of miRNome Identifies Novel Candidate miRNA-mRNA Interactions Implicated in T-Cell Acute Lymphoblastic Leukemia.
Neoplasia. 2019; 21(3):294-310 [PubMed] Free Access to Full Article Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6-mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3' untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.

Cruz-Miranda GM, Hidalgo-Miranda A, Bárcenas-López DA, et al.
Long Non-Coding RNA and Acute Leukemia.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Acute leukemia (AL) is the main type of cancer in children worldwide. Mortality by this disease is high in developing countries and its etiology remains unanswered. Evidences showing the role of the long non-coding RNAs (lncRNAs) in the pathophysiology of hematological malignancies have increased drastically in the last decade. In addition to the contribution of these lncRNAs in leukemogenesis, recent studies have suggested that lncRNAs could be used as biomarkers in the diagnosis, prognosis, and therapeutic response in leukemia patients. The focus of this review is to describe the functional classification, biogenesis, and the role of lncRNAs in leukemogenesis, to summarize the evidence about the lncRNAs which are playing a role in AL, and how these genes could be useful as potential therapeutic targets.

Poulard C, Kim HN, Fang M, et al.
Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia.
Proc Natl Acad Sci U S A. 2019; 116(8):3052-3061 [PubMed] Free Access to Full Article Related Publications
Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics.

Valiollahi E, Ribera JM, Genescà E, Behravan J
Genome-wide identification of microRNA signatures associated with stem/progenitor cells in Philadelphia chromosome-positive acute lymphoblastic leukemia.
Mol Biol Rep. 2019; 46(1):1295-1306 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph

Zarubina KI, Parovichnikova EN, Baskhaeva GA, et al.
Diagnostics and treatment challenges of Ph-like acute lymphoblastic leukemia: a description of 3 clinical cases.
Ter Arkh. 2018; 90(7):110-117 [PubMed] Related Publications
B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured: refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase). The remission in these patients was achieved after chemotherapy change to immunological targeted therapy. Nowadays a unified therapeutic approach to all primary patients of the B-ALL is considered generally outdated. Great efforts are carrying out to develop molecular genetic classifications. The molecular dissection of subtypes of B-ALL goes on, and new protocols for selective treatment with targeting are clearly outlined for each subtype of B-ALL.

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