ALL - Molecular Biology

Overview

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 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (146)

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'.

GeneLocationAliasesNotesTopicPapers
BCR 22q11.23 ALL, CML, PHL, BCR1, D22S11, D22S662 Translocation
-BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
-BCR and Acute Lymphocytic Leukaemia
974
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Acute Lymphocytic Leukaemia
229
MLLT10 10p12 AF10 Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
-t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia
122
CD34 1q32 -CD34 and Acute Lymphocytic Leukaemia
186
PBX1 1q23 -PBX1 and Acute Lymphocytic Leukaemia
148
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
122
KITLG 12q22 SF, MGF, SCF, FPH2, FPHH, KL-1, Kitl, SHEP7 -KITLG and Acute Lymphocytic Leukaemia
139
MTHFR 1p36.22 -MTHFR and Acute Lymphocytic Leukaemia
139
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Acute Leukaemias
125
IKZF1 7p12.2 IK1, LYF1, LyF-1, IKAROS, PPP1R92, PRO0758, ZNFN1A1, Hs.54452 -IKZF1 and Acute Lymphocytic Leukaemia
124
CD33 19q13.41 p67, SIGLEC3, SIGLEC-3 -CD33 and Acute Lymphocytic Leukaemia
97
PICALM 11q14.2 LAP, CALM, CLTH Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
76
CD9 12p13.3 MIC3, MRP-1, BTCC-1, DRAP-27, TSPAN29, TSPAN-29 -CD9 and Acute Lymphocytic Leukaemia
71
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2, RHEPDGFRA Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
66
FIP1L1 4q12 Rhe, FIP1, hFip1 Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
66
CDKN2B 9p21 P15, MTS2, TP15, CDK4I, INK4B, p15INK4b -CDKN2B and Acute Lymphocytic Leukaemia
64
LMO2 11p13 TTG2, RBTN2, RHOM2, RBTNL1 -LMO2 and T-Cell Acute Lymphocytic Leukaemia
63
HLF 17q22 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
-HLF and Acute Lymphocytic Leukaemia
34
CRLF2 Xp22.3; Yp11.3 CRL2, TSLPR, CRLF2Y -CRLF2 and Acute Lymphocytic Leukaemia
60
ETV6 12p13 TEL, THC5, TEL/ABL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
-t(12;21) in Adult Lyphocytic Leukaemia
35
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)
43
TRG 7p14 TCRG, TRG@ -TRG and Acute Lymphoblastic Leukemia
37
TLX1 10q24 TCL3, HOX11 -TLX1 and Acute Lymphocytic Leukaemia
37
CD22 19q13.1 SIGLEC2, SIGLEC-2 -CD22 and Acute Lymphocytic Leukaemia
37
ABL1 9q34.1 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
35
NUP214 9q34.1 CAN, CAIN, N214, p250, D9S46E Translocation
-NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
35
RUNX1 21q22.3 AML1, CBFA2, EVI-1, AMLCR1, PEBP2aB, AML1-EVI-1 Translocation
-t(12;21) in Adult Lyphocytic Leukaemia
35
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
34
SLC19A1 21q22.3 CHMD, FOLT, IFC1, REFC, RFC1 -SLC19A1 and Acute Lymphocytic Leukaemia
34
TCF3 19p13.3 E2A, E47, ITF1, VDIR, TCF-3, bHLHb21 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
34
JAK1 1p32.3-p31.3 JTK3, JAK1A, JAK1B -JAK1 and Acute Lymphocytic Leukaemia
29
IGK 2p12 IGK@ -IGK and Acute Lymphocytic Leukaemia
29
TLX3 5q35.1 RNX, HOX11L2 -TLX3 and Acute Lymphocytic Leukaemia
28
CD79A 19q13.2 IGA, MB-1 -CD79A and Acute Lymphocytic Leukaemia
27
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Acute Lymphocytic Leukaemia
26
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Acute Lymphocytic Leukaemia
26
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Acute Lymphocytic Leukaemia
26
TAL1 1p32 SCL, TCL5, tal-1, bHLHa17 -TAL1 and Acute Lymphocytic Leukaemia
24
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
17
TPMT 6p22.3 -TPMT and Acute Lymphocytic Leukaemia
24
CYP1A1 15q24.1 AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX -CYP1A1 and Acute Lymphocytic Leukaemia
24
ELL 19p13.1 MEN, ELL1, PPP1R68, C19orf17 Translocation
-ELL and Acute Lymphocytic Leukaemia
-t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia
18
DHFR 5q14.1 DYR, DHFRP1 -DHFR and Acute Lymphocytic Leukaemia
22
STAM 10p14-p13 STAM1, STAM-1 -STAM and Acute Lymphocytic Leukaemia
22
ABL2 1q25.2 ARG, ABLL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
21
P2RY8 Xp22.33; Yp11.3 P2Y8 -P2RY8 and Acute Lymphocytic Leukaemia
20
CEBPE 14q11.2 CRP1, C/EBP-epsilon -CEBPE and Acute Lymphocytic Leukaemia
20
HLA-DRB1 6p21.3 SS1, DRB1, DRw10, HLA-DRB, HLA-DR1B -HLA-DRB1 and Acute Lymphocytic Leukaemia
20
EBF1 5q34 EBF, COE1, OLF1, O/E-1 -EBF1 and Acute Lymphocytic Leukaemia
19
CD14 5q31.1 -CD14 and Acute Lymphocytic Leukaemia
19
GALE 1p36-p35 SDR1E1 -GALE and Acute Lymphocytic Leukaemia
18
ABCG2 4q22 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, CDw338, UAQTL1, EST157481 -ABCG2 and Acute Lymphocytic Leukaemia
18
JAK3 19p13.1 JAKL, LJAK, JAK-3, L-JAK, JAK3_HUMAN -JAK3 and Acute Lymphocytic Leukaemia
18
TYMS 18p11.32 TS, TMS, HST422 -TYMS and Acute Lymphocytic Leukaemia
17
JAK2 9p24.1 JTK10, THCYT3 -JAK2 mutations in Down syndrome-associated ALL
17
LMO1 11p15.4 TTG1, RBTN1, RHOM1 -LMO1 and T-Cell Leukemia-Lymphoma
16
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Acute Lymphoblastic Leukaemia
15
RFC1 4p14-p13 A1, RFC, PO-GA, RECC1, MHCBFB, RFC140 -RFC1 and Acute Lymphocytic Leukaemia
15
IL7R 5p13 ILRA, CD127, IL7RA, CDW127, IL-7R-alpha -IL7R and Acute Lymphocytic Leukaemia
14
FHIT 3p14.2 FRA3B, AP3Aase -FHIT and Acute Lymphocytic Leukaemia
14
MCL1 1q21 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Acute Lymphocytic Leukaemia
12
CD1A 1q23.1 R4, T6, CD1, FCB6, HTA1 -CD1A and Acute Lymphocytic Leukaemia
11
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Acute Lymphocytic Leukaemia
10
SLCO1B1 12p LST1, HBLRR, LST-1, OATP2, OATPC, OATP-C, OATP1B1, SLC21A6 -SLCO1B1 and Acute Lymphocytic Leukaemia
10
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Acute Lymphocytic Leukaemia
10
RAG2 11p12 RAG-2 -RAG2 and Acute Lymphocytic Leukaemia
10
RAG1 11p12 RAG-1, RNF74 -RAG1 and Acute Lymphocytic Leukaemia
9
FPGS 9q34.1 -FPGS and Acute Lymphocytic Leukaemia
9
BTG1 12q22 -BTG1 and Acute Lymphocytic Leukaemia
8
CASP8AP2 6q15 CED-4, FLASH, RIP25 -CASP8AP2 and Acute Lymphocytic Leukaemia
8
MTAP 9p21 BDMF, MSAP, DMSFH, LGMBF, DMSMFH, c86fus, HEL-249 -MTAP and Acute Lymphocytic Leukaemia
8
TCF7L1 2p11.2 TCF3, TCF-3 -TCF7L1 and Acute Lymphocytic Leukaemia
8
MTHFD1 14q24 MTHFC, MTHFD -MTHFD1 and Acute Lymphocytic Leukaemia
8
STIL 1p32 SIL, MCPH7 -STIL and Adult T-Cell Leukemia-Lymphoma
8
IL15 4q31 IL-15 -IL15 and Acute Lymphocytic Leukaemia
8
MLLT1 19p13.3 ENL, LTG19, YEATS1 -MLLT1 and Acute Lymphocytic Leukaemia
8
CD79B 17q23 B29, IGB, AGM6 -CD79B and Acute Lymphocytic Leukaemia
8
HLA-DPB1 6p21.3 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Acute Lymphocytic Leukaemia
8
HFE 6p21.3 HH, HFE1, HLA-H, MVCD7, TFQTL2 -HFE and Acute Lymphocytic Leukaemia
7
HOXA7 7p15.2 ANTP, HOX1, HOX1A, HOX1.1 -HOXA7 and Acute Lymphocytic Leukaemia
7
MLLT3 9p22 AF9, YEATS3 -MLLT3 and Acute Lymphocytic Leukaemia
7
CEACAM6 19q13.2 NCA, CEAL, CD66c -CEACAM6 and Acute Lymphocytic Leukaemia
7
MEF2C 5q14.3 DEL5q14.3, C5DELq14.3 -MEF2C and Acute Lymphocytic Leukaemia
6
OLAH 10p13 SAST, AURA1, THEDC1 -OLAH and Acute Lymphocytic Leukaemia
6
PMS2 7p22.1 MLH4, PMSL2, HNPCC4, PMS2CL -PMS2 and Acute Lymphocytic Leukaemia
6
IDH1 2q33.3 IDH, IDP, IDCD, IDPC, PICD, HEL-216, HEL-S-26 -IDH1 and Acute Lymphocytic Leukaemia
6
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Acute Lymphocytic Leukaemia
6
ABCC2 10q24 DJS, MRP2, cMRP, ABC30, CMOAT -ABCC2 and Acute Lymphocytic Leukaemia
5
TYK2 19p13.2 JTK1, IMD35 -TYK2 and Acute Lymphocytic Leukaemia
5
ABCC4 13q32 MRP4, MOATB, MOAT-B -ABCC4 and Acute Lymphocytic Leukaemia
5
BIRC7 20q13.3 KIAP, LIVIN, MLIAP, RNF50, ML-IAP -BIRC7 and Acute Lymphocytic Leukaemia
5
CCNC 6q21 CycC -CCNC and Acute Lymphocytic Leukaemia
5
SLC29A1 6p21.1 ENT1 -SLC29A1 and Acute Lymphocytic Leukaemia
5
AFF3 2q11.2-q12 LAF4, MLLT2-like -AFF3 and Acute Lymphocytic Leukaemia
5
BCL2L11 2q13 BAM, BIM, BOD -BCL2L11 and Acute Lymphocytic Leukaemia
5
CTLA4 2q33 CD, GSE, GRD4, ALPS5, CD152, CTLA-4, IDDM12, CELIAC3 -CTLA4 and Acute Lymphocytic Leukaemia
5
GAST 17q21 GAS -GAST and Acute Lymphocytic Leukaemia
5
TFPT 19q13.42 FB1, amida, INO80F -TFPT and Acute Lymphocytic Leukaemia
4
NOD2 16q21 CD, ACUG, BLAU, IBD1, NLRC2, NOD2B, CARD15, CLR16.3, PSORAS1 -NOD2 and Acute Lymphocytic Leukaemia
4
PTPRG 3p21-p14 PTPG, HPTPG, RPTPG, R-PTP-GAMMA -PTPRG and Acute Lymphocytic Leukaemia
4
SLC19A2 1q23.3 TC1, THT1, TRMA, THMD1, THTR1 -SLC19A2 and Acute Lymphocytic Leukaemia
4
PBX3 9q33.3 -PBX3 and Acute Lymphocytic Leukaemia
4
CD83 6p23 BL11, HB15 -CD83 and Acute Lymphocytic Leukaemia
4
RANBP17 5q34 -RANBP17 and Acute Lymphocytic Leukaemia
4
CD3D 11q23.3 T3D, IMD19, CD3-DELTA -CD3D and Acute Lymphocytic Leukaemia
4
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Acute Lymphocytic Leukaemia
4
ZNF384 12p12 NP, CIZ, NMP4, CAGH1, ERDA2, TNRC1, CAGH1A -ZNF384 and Acute Lymphocytic Leukaemia
4
TET1 10q21 LCX, CXXC6, bA119F7.1 Translocation
-t(10;11) MLL-TET1 rearrangement in acute leukemias
4
CD69 12p13 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Acute Lymphocytic Leukaemia
3
TNFRSF8 1p36 CD30, Ki-1, D1S166E -TNFRSF8 and Acute Lymphocytic Leukaemia
3
CD58 1p13 ag3, LFA3, LFA-3 -CD58 and Acute Lymphocytic Leukaemia
3
PTER 10p12 HPHRP, RPR-1 -PTER and Acute Lymphocytic Leukaemia
3
HCK 20q11-q12 JTK9, p59Hck, p61Hck -HCK and Acute Lymphocytic Leukaemia
3
NNAT 20q11.2-q12 Peg5 -NNAT and Acute Lymphocytic Leukaemia
3
MIR126 9q34.3 MIRN126, mir-126, miRNA126 -MicroRNA mir-126 and Acute Lymphocytic Leukaemia
3
CHFR 12q24.33 RNF116, RNF196 -CHFR and Acute Lymphocytic Leukaemia
3
LRRC3B 3p24 LRP15 -LRRC3B and Acute Lymphocytic Leukaemia
2
MLLT6 17q21 AF17 -MLLT6 and Acute Lymphocytic Leukaemia
2
ZNF521 18q11.2 EHZF, Evi3 -ZNF521 and Acute Lymphocytic Leukaemia
2
TTL 2q13 -TTL and Acute Lymphocytic Leukaemia
2
SERPINC1 1q25.1 AT3, AT3D, ATIII, THPH7 -SERPINC1 and Acute Lymphocytic Leukaemia
2
CTNND1 11q12.1 CAS, p120, CTNND, P120CAS, P120CTN, p120(CAS), p120(CTN) -CTNND1 and Acute Lymphocytic Leukaemia
2
TFRC 3q29 T9, TR, TFR, p90, CD71, TFR1, TRFR -TFRC and Acute Lymphocytic Leukaemia
2
CDK2AP1 12q24.31 DOC1, ST19, DORC1, doc-1, p12DOC-1 -CDK2AP1 and Acute Lymphocytic Leukaemia
2
MNX1 7q36 HB9, HLXB9, SCRA1, HOXHB9 -MNX1 and Acute Lymphocytic Leukaemia
2
GSTO1 10q25.1 P28, SPG-R, GSTO 1-1, GSTTLp28, HEL-S-21 -GSTO1 and Acute Lymphocytic Leukaemia
2
CD55 1q32 CR, TC, DAF, CROM -CD55 and Acute Lymphocytic Leukaemia
2
BLNK 10q23.2-q23.33 bca, AGM4, BASH, LY57, SLP65, BLNK-S, SLP-65 -BLNK and Acute Lymphocytic Leukaemia
2
SFPQ 1p34.3 PSF, POMP100, PPP1R140 -SFPQ and Acute Lymphocytic Leukaemia
1
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Acute Lymphocytic Leukaemia
1
TPD52L1 6q22-q23 D53, hD53 -TPD52L1 and Acute Lymphocytic Leukaemia
1
PRTN3 19p13.3 MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA -PRTN3 and Acute Lymphocytic Leukaemia
1
ARHGEF12 11q23.3 LARG, PRO2792 -ARHGEF12 and Acute Lymphocytic Leukaemia
1
FCRL4 1q21 FCRH4, IGFP2, IRTA1, CD307d -FCRL4 and Acute Lymphocytic Leukaemia
1
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Acute Lymphocytic Leukaemia
1
ARHGAP26 5q31 GRAF, GRAF1, OPHN1L, OPHN1L1 -ARHGAP26 and Acute Lymphocytic Leukaemia
1
RASSF10 11p15.3 -RASSF10 and Acute Lymphocytic Leukaemia
1
DOK2 8p21.3 p56DOK, p56dok-2 -DOK2 and Acute Lymphocytic Leukaemia
1
ADIPOQ 3q27 ACDC, ADPN, APM1, APM-1, GBP28, ACRP30, ADIPQTL1 -ADIPOQ and Acute Lymphocytic Leukaemia
1
RASSF6 4q13.3 -RASSF6 and Acute Lymphocytic Leukaemia
1
ACKR3 2q37.3 RDC1, CXCR7, RDC-1, CMKOR1, CXC-R7, CXCR-7, GPR159 -ACKR3 and Acute Lymphocytic Leukaemia
1
FCGR2B 1q23 CD32, FCG2, CD32B, FCGR2, IGFR2 -FCGR2B and Acute Lymphocytic Leukaemia
1
DPH1 17p13.3 DPH2L, OVCA1, DPH2L1 -DPH1 and Acute Lymphocytic Leukaemia
1
LYL1 19p13.2 bHLHa18 Translocation
-t(7;19)(q35;p13) in T-cell Acute Lymphoblastic Leukemia
BCL2 18q21.3 Bcl-2, PPP1R50 Translocation
-t(14;18)(q32;q21) in Acute Lymphoblastic Leukaemia
AFF1 4q21 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

Shabestari RM, Safa M, Alikarami F, et al.
CREB knockdown inhibits growth and induces apoptosis in human pre-B acute lymphoblastic leukemia cells through inhibition of prosurvival signals.
Biomed Pharmacother. 2017; 87:274-279 [PubMed] Related Publications
A majority of acute lymphoblastic leukemia patients overexpress CREB in the bone marrow. However, the functional significance of this up-regulation and the detailed molecular mechanism behind the regulatory effect of CREB on the growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells has not been elucidated. We demonstrated here that CREB knockdown induced apoptosis and impaired growth of BCP-ALL NALM-6 cells which was associated with caspase activation. The gene expression levels of prosurvival signals Bcl-2, Mcl-1, Bcl-xL, survivin and XIAP were down-regulated upon CREB suppression. These findings indicate a critical role for CREB in proliferation, survival, and apoptosis of BCP-ALL cells. The data also suggest that CREB could possibly serve as potential therapeutic target in BCP-ALL.

Zhang B, Zhang W, Yan L, Wang D
The association between MTHFR gene C677T polymorphism and ALL risk based on a meta-analysis involving 17,469 subjects.
Clin Chim Acta. 2017; 466:85-92 [PubMed] Related Publications
BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is closely related to the acute lymphoblastic leukaemia (ALL) indicated by many previous epidemiologic studies. However, their conclusions were still conflicting.
METHODS: Our aim is to evaluate their associations using a more comprehensive updated meta-analysis. Electronic searches were conducted to select published studies prior to February, 2016.
RESULTS: Totally, 39 case-control studies including 6551 ALL cases and 10,918 controls were selected in current meta-analysis. The association was detected significantly between MTHFR C677T polymorphism and ALL reducing susceptibility.
CONCLUSIONS: Our results indicate that the MTHFR C677T polymorphism may be a promising ALL biomarker and studies to explore the protein levels of the variants and their functional role are required for the definitive conclusions.

Eskandari-Nasab E, Hashemi M, Hasani SS, et al.
Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia-A case-control study from Iran.
Nucleosides Nucleotides Nucleic Acids. 2017; 36(3):170-180 [PubMed] Related Publications
We examined the possible relationship between three RAGE polymorphisms, -429C/T, -374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE -374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.

Serravalle S, Bertuccio SN, Astolfi A, et al.
Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature.
Biomed Res Int. 2016; 2016:1985750 [PubMed] Free Access to Full Article Related Publications
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression.

Singh SK, Lupo PJ, Scheurer ME, et al.
A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.
Medicine (Baltimore). 2016; 95(46):e5300 [PubMed] Free Access to Full Article Related Publications
Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

Zhang W, Kuang P, Li H, et al.
Prognostic significance of IKZF1 deletion in adult B cell acute lymphoblastic leukemia: a meta-analysis.
Ann Hematol. 2017; 96(2):215-225 [PubMed] Related Publications
The IKAROS family zinc finger 1 (IKZF1) gene is frequently altered in adults with B cell acute lymphoblastic leukemia (ALL). Although many studies have indicated that IKZF1 alterations might be associated with poor outcomes in adults with ALL, the results remain controversial. A previous meta-analysis demonstrated the negative prognostic significance of IKZF1 deletion in ALL. However, most of the included studies (14 out of 15) were conducted in pediatric patients with ALL, and age was identified as a significant source of heterogeneity. Thus, performing the present meta-analysis provides valuable information to further elucidate the prognostic value of IKZF1 deletion in adults with ALL. Eight studies were identified that had been published prior to August 1, 2016. The studies included a total of 1008 patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/progression-free survival (PFS)/event-free survival (EFS) were pooled to estimate the prognostic power of IKZF1 deletion. Pooled HRs suggested that IKZF1 deletion had a negative impact on both OS (HR = 1.40, 95% CI 1.13-1.73) and DFS/RFS/PFS/EFS (HR = 1.67, 95% CI 1.28-2.17) in the overall population. Subgroup analyses indicated that IKZF1 deletion could independently predict unfavorable OS (HR = 1.60, 95% CI 1.25-2.06) and DFS/RFS/PFS/EFS (HR = 1.67, 95% CI 1.28-2.17) in BCR-ABL1-negative but not in BCR-ABL1-positive B cell ALL patients. Our meta-analysis suggests that IKZF1 deletion is a poor prognostic factor for adults with B cell ALL and may be more valuable in BCR-ABL1-negative B cell ALL patients.

Yilmaz UC, Bagca BG, Karaca E, et al.
Evaluation of the miRNA profiling and effectiveness of the propolis on B-cell acute lymphoblastic leukemia cell line.
Biomed Pharmacother. 2016; 84:1266-1273 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is one of the most frequent causes of death from cancer. Since the discovery of chemotherapeutic agents, ALL has become a model for improvement of survival. In parallel to this, serious side effects were observed and new natural therapeutic options has been discussed. One of these substances is called propolis which is a resinous substance gathered by honeybees. In the molecular era, miRNAs have been shown to play crucial roles in the development of many clinical conditions. The aim of this study is to evaluate the effect of Aydın propolis on 81 human miRNA activity in CCRF-SB leukemia cell line. Apoptotic effects of propolis on cell lines were also evaluated and apoptosis were found to be induced 1.5 fold in B-cell leukemia cells. The expression of 63 miRNAs (46 miRNAs were downregulated, 19 miRNAs were upregulated) in propolis treated leukemia cells have changed significantly (p<0.05). In conclusion propolis has changed expression of miRNAs which have epigenetic effects on leukemic cells. It is thought that it can be a promising agent for ALL treatment for future studies.

Al-Ghobashy MA, Hassan SA, Abdelaziz DH, et al.
Development and validation of LC-MS/MS assay for the simultaneous determination of methotrexate, 6-mercaptopurine and its active metabolite 6-thioguanine in plasma of children with acute lymphoblastic leukemia: Correlation with genetic polymorphism.
J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1038:88-94 [PubMed] Related Publications
Individualized therapy is a recent approach aiming to specify dosage regimen for each patient according to its genetic state. Cancer chemotherapy requires continuous monitoring of the plasma concentration levels of active forms of cytotoxic drugs and subsequent dose adjustment. In order to attain optimum therapeutic efficacy, correlation to pharmacogenetics data is crucial. In this study, a specific, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for determination of methotrexate (MTX), 6-mercaptopurine (MP) and its metabolite 6-thioguanine nucleotide (TG) in human plasma. Based on the basic character of the studied compounds, solid phase extraction using a strong cation exchanger was found the optimum approach to achieve good extraction recovery. Chromatographic separation was carried out using RP-HPLC and isocratic elution by acetonitrile: 0.1% aqueous formic acid (85:15v/v) with a flow rate of 0.8mL/min at 40°C. The detection was performed by tandem mass spectrometry in MRM mode via electrospray ionization source in positive ionization mode. Analysis was carried out within 1.0min over a concentration range of 6.25-200.00ng/mL for the studied analytes. Validation was carried out according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the monitoring of the MTX, MP and TG and subsequent application to personalized therapy was demonstrated in a clinical study on children with acute lymphoblastic leukemia (ALL). Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.

Yamamoto K, Kawamoto S, Mizutani Y, et al.
Mixed Phenotype Acute Leukemia with t(12;17)(p13;q21)/TAF15-ZNF384 and Other Chromosome Abnormalities.
Cytogenet Genome Res. 2016; 149(3):165-170 [PubMed] Related Publications
The t(12;17)(p13;q11∼21) translocation is a very rare but recurrent cytogenetic aberration observed predominantly in early pre-B acute lymphoblastic leukemia (ALL) with CD19+CD10-CD33+ phenotype. This translocation was shown to form a fusion gene between TAF15 at 17q12 and ZNF384 at 12p13. On the other hand, der(1;18)(q10;q10) has been detected as a rare unbalanced whole-arm translocation leading to trisomy 1q in myeloid malignancies. We describe here the first case of mixed phenotype acute leukemia (MPAL) with a t(12;17)(p13;q21)/TAF15-ZNF384, which also had der(1;18)(q10;q10) as an additional abnormality. A 74-year-old woman was diagnosed with MPAL, B/myeloid, because bone marrow blasts were positive for myeloperoxidase, CD19, and CD22. Chromosome analysis showed 46,XX, +1,der(1;18)(q10;q10),t(2;16)(q13;q13),t(12;17)(p13;q21). Expression of the TAF15-ZNF384 fusion transcript was confirmed: TAF15 exon 6 was fused in-frame to ZNF384 exon 3. This type of fusion gene has been reported in 1 acute myeloid leukemia case and 3 ALL cases. Thus, at present, it is difficult to find a specific association between the structure of the TAF15-ZNF384 fusion gene and the leukemia phenotype. The TAF15-ZNF384 fusion may occur in early common progenitor cells that could differentiate into both the myeloid and lymphoid lineages. Furthermore, der(1;18)(q10;q10) might play some role in the appearance of an additional myeloid phenotype.

Ittel A, Zattara H, Chaix C, et al.
Molecular combing: A new tool in diagnosing leukemia.
Cancer Biomark. 2016; 17(4):405-409 [PubMed] Related Publications
BACKGROUND: According to the World Health Organization (WHO), recurrent cytogenetic abnormalities define many specific groups of hematopoietic tumors of acute myeloid and lymphoblastic leukemia, and these abnormalities are often strongly associated with prognosis and sometimes require specific treatments. These rearrangements are commonly detected by conventional and molecular cytogenetic techniques.
OBJECTIVE: Using an alternative method, we sought to highlight the presence of chromosomal rearrangements.
METHODS: We applied molecular combing to detect and directly visualize gene fusions associated with balanced translocations found in acute leukemia.
RESULTS: In patients harboring t(12;21)(p13;q22), we demonstrated the presence of the fusion using specific probes covering the ETV6 and RUNX1 genes, with a positive result occurring due to the hybridization of the two probes to the same DNA fiber. Thanks to molecular combing, we also showed the presence of different breakpoints using these same probes.
CONCLUSIONS: Using several probes that are specific to the most common genes involved in acute leukemia, molecular combing could be an interesting additional tool in acute leukemia diagnosis.

Pei JS, Hsu PC, Chou AK, et al.
Matrix Metalloproteinase-1 Genotype Contributes to the Risk of Non-solid Tumor in Childhood Leukemia.
Anticancer Res. 2016; 36(10):5127-5132 [PubMed] Related Publications
AIM: Up-regulation of metalloproteinase (MMPs) proteins have been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. However, the contribution of MMP1 genotype to leukemia has never been investigated to our knowledge. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP1 to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan.
MATERIALS AND METHODS: In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology.
RESULTS: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter rs1799750 genotype was 49.2%, 39.5% and 11.3% in the childhood ALL group and 36.8%, 43.6% and 19.5% in the non-cancer control group, respectively (p for trend=0.0046), significantly differentially distributed between childhood ALL and control groups. The carrier comparisons in dominant and recessive models also support the findings that 1G appears to be the protective allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP1 rs1799750 1G/2G or 1G/1G genotypes had lower odds ratios(ORs) of 0.68 and 0.43 [95% confidence intervals (CI)=0.47-0.98 and 0.26-0.73, p=0.0395 and 0.0013, respectively] for childhood ALL than those carrying the 2G/2G genotype. Analysis of genotype inaction with age of onset age showed those aged less than 3.5 years at onset carrying the 1G/2G or 1G/1G genotypes had lower ORs (0.0183 and 0.0004, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more.
CONCLUSION: Our results indicate that the MMP1 rs1799750 1G allele is a protective biomarker for childhood ALL.

Mousavian Z, Nowzari-Dalini A, Stam RW, et al.
Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia.
Cell Oncol (Dordr). 2017; 40(1):33-45 [PubMed] Related Publications
PURPOSE: Despite vast improvements that have been made in the treatment of children with acute lymphoblastic leukemia (ALL), the majority of infant ALL patients (~80 %, < 1 year of age) that carry a chromosomal translocation involving the mixed lineage leukemia (MLL) gene shows a poor response to chemotherapeutic drugs, especially glucocorticoids (GCs), which are essential components of all current treatment regimens. Although addressed in several studies, the mechanism(s) underlying this phenomenon have remained largely unknown. A major drawback of most previous studies is their primary focus on individual genes, thereby neglecting the putative significance of inter-gene correlations. Here, we aimed at studying GC resistance in MLL-rearranged infant ALL patients by inferring an associated module of genes using co-expression network analysis. The implications of newly identified candidate genes with associations to other well-known relevant genes from the same module, or with associations to known transcription factor or microRNA interactions, were substantiated using literature data.
METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with GC resistance in MLL-rearranged infant ALL patients. Significant gene ontology (GO) terms and signaling pathways enriched in relevant modules were used to provide guidance towards which module(s) consisted of promising candidates suitable for further analysis.
RESULTS: Through gene co-expression network analysis a novel set of genes (module) related to GC-resistance was identified. The presence in this module of the S100 and ANXA genes, both well-known biomarkers for GC resistance in MLL-rearranged infant ALL, supports its validity. Subsequent gene set net correlation analyses of the novel module provided further support for its validity by showing that the S100 and ANXA genes act as 'hub' genes with potentially major regulatory roles in GC sensitivity, but having lost this role in the GC resistant phenotype. The detected module implicates new genes as being candidates for further analysis through associations with known GC resistance-related genes.
CONCLUSIONS: From our data we conclude that available systems biology approaches can be employed to detect new candidate genes that may provide further insights into drug resistance of MLL-rearranged infant ALL cases. Such approaches complement conventional gene-wise approaches by taking putative functional interactions between genes into account.

Chiaretti S, Foà R
How has the management of Ph(+) acute lymphoblastic leukemia (ALL) changed over the years.
Rinsho Ketsueki. 2016; 57(10):2038-2048 [PubMed] Related Publications
For decades, Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been considered the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL and, in the elderly, it accounts for approximately 50% of cases. The introduction of tyrosine kinase inhibitors (TKIs) has led to obtain complete hematologic remissions (CHR) in virtually all patients, to improve disease-free survival and overall survival, and to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo-SCT). Thus, the current management of adult Ph+ ALL patients is based on the use of a TKI, with or without systemic chemotherapy, followed by an allo-SCT, which still remains the only curative option. Monitoring of minimal residual disease allowed a better stratification of patients, and also enabled to redefine the role of autologous stem cell transplant for patients who do not have a donor or are unfit for an allo-transplant. The main clinical challenges are today represented by the emergence of resistant mutations, particularly the gatekeeper T315I, for which alternative approaches, including novel TKIs and/or therapies based on the combination of TKI with immunotherapeutic strategies, are being considered.

Inukai T
Mechanisms of drug resistance in acute lymphoblastic leukemia.
Rinsho Ketsueki. 2016; 57(10):2022-2028 [PubMed] Related Publications
Outcomes of patients with acute lymphoblastic leukemia (ALL) have improved dramatically with conventional chemotherapy consisting of multiple agents. However, considering the major impact of tyrosine kinase inhibitors in the treatment of Philadelphia chromosome-positive ALL, sensitivities to each chemotherapeutic agent must be appreciated in individual cases to further improve therapeutic outcomes of ALL patients. Recent advances in genome-wide association and comprehensive genetic mutation studies with next-generation sequencing enable the involvement of single nucleotide polymorphisms and acquired genetic mutations in the drug resistance of ALL to be evaluated. Herein, we overview recent findings regarding the mechanisms of drug resistance in ALL. Our observations in a large panel of ALL cell lines are also presented.

Besbes S, Hamadou WS, Boulland ML, et al.
Combined IKZF1 and IG markers as new tools for diagnosis and minimal residual disease assessment in Tunisian B-ALL.
Bull Cancer. 2016; 103(10):822-828 [PubMed] Related Publications
INTRODUCTION: The monitoring of minimal residual disease (MRD) approach in patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) allows an early detection of residual clones inducing relapses and therefore appropriate therapy strategy. The molecular markers may identify and quantify the residual blasts in B-ALL with normal cytology. In this study, we aimed to use combined IKZF1, IGH and IGK immunoglobulin genes for diagnosis and MRD monitoring in B-ALL sample using MLPA, multiplex PCR and real-time quantitative PCR.
MATERIAL: We showed that multiplex PCR and MLPA are necessary and complementary to detect IKZF1 deletions.
RESULTS: We have identified at the diagnosis clonal IGH rearrangement (VH3-JH5) and IKZF1 deletion (Δ4-7), which we have used it for MRD evaluation after induction chemotherapy. Despite the absence of chromosome abnormality, the patient may be classified in high-risk group with a relapse rate of residual blasts>10(-4) and sensitivity up to 10(-5). This molecular approach enabled the patient's stratification, which was overlooked by classical methods.
CONCLUSION: The combined IKZF1 and immunoglobulin genes will be used as appropriate molecular tools for diagnosis and MRD assessment of B-lineage leukemias and introduced as a routine tests in Tunisian clinical laboratories. They will be useful to stratify patients into risk groups leading to better treatment strategy.

Liljevald M, Rehnberg M, Söderberg M, et al.
Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma.
Autoimmun Rev. 2016; 15(11):1062-1070 [PubMed] Related Publications
RORγ is a nuclear hormone receptor which controls polarization of naive CD4(+) T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORγ has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORγ, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORγ during development, the Rorc knockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation of CD4+ and CD8+ T cells. We wanted to extend the evaluation of RORγ deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional RORγ knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma.

Ramírez-Pacheco A, Moreno-Guerrero S, Alamillo I, et al.
Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes.
Genet Test Mol Biomarkers. 2016; 20(10):597-602 [PubMed] Related Publications
BACKGROUND: Genetic polymorphisms in patients with acute lymphoblastic leukemia (ALL) may influence the toxicity of chemotherapeutic agents. Due to the importance of the transport P-glycoprotein and methylenetetrahydrofolate reductase in the metabolism of chemotherapeutic agents, we analyzed the MDR1 rs1045642 and MTHFR rs1801133 polymorphisms and their associations with clinical outcomes in Mexican childhood ALL patients.
METHODS: A total of 109 patients participated in this study. The clinical evaluation consisted of a physical examination and a laboratory test. Genotyping of MDR1 rs1045642 (3435 C>T) and MTHFR rs1801133 (677 C>T) was performed by polymerase chain reaction/restriction fragment length polymorphism. Statistical analyses were performed using SPSS 14.0. The odds ratios and 95% confidence intervals (CI) were estimated by logistic regression.
RESULTS: Individuals who were CC homozygotes at MDR1 rs1045642 had lower risk of having methotrexate plasma concentrations >1 μM and leukopenia grade I (odds ratio [OR] = 0.30; 95% CI = 0.13-0.72 and OR = 0.32; 95% CI = 0.14-0.72, respectively). Patients who were CC homozygotes at MTHFR rs1801133 had a higher risk of developing mucositis (OR = 3.61; 95% CI = 1.42-9.14).
CONCLUSION: MDR1 rs1045642 and MTHFR rs1801133 should be considered as diagnostic candidates for the identification of pediatric patients with a high risk of suffering adverse events during ALL treatment.

Wu X, Feng X, Zhao X, et al.
Role of Beclin-1-Mediated Autophagy in the Survival of Pediatric Leukemia Cells.
Cell Physiol Biochem. 2016; 39(5):1827-1836 [PubMed] Related Publications
BACKGROUND/AIMS: Acute and chronic leukemia are severe malignant cancers worldwide, and can occur in pediatric patients. Since bone marrow cell transplantation is seriously limited by the availability of the immune-paired donor sources, the therapy for pediatric leukemia (PL) remains challenging. Autophagy is essential for the regulation of cell survival in the harsh environment. However, the role of autophagy in the survival of PL cells under the oxidative stress, e.g. chemotherapy, remain ill-defined. In the current study, we addressed these questions.
METHODS: We analyzed the effects of oxidative stress on the cell viability of PL cells in vitro, using a CCK-8 assay. We analyzed the effects of oxidative stress on the apoptosis and autophagy of PL cells. We analyzed the levels of Beclin-1 and microRNA-93 (miR-93) in PL cells. Prediction of binding between miR-93 and 3'-UTR of Beclin-1 mRNA was performed by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The relationship between levels of miR-93 and patients' survival was analyzed in PL patients.
RESULTS: We found that oxidative stress dose-dependently increased autophagy in PL cells. While low-level oxidative stress did not increase apoptosis, high-level oxidative stress increased apoptosis, seemingly from failure of autophagy-mediated cell survival. High-level oxidative stress appeared to suppress the protein levels of an autophagy protein Beclin-1 in PL cells, possibly through induction of miR-93, which inhibited the translation of Beclin-1 mRNA via 3'-UTR binding.
CONCLUSION: Beclin-1-mediated autophagy plays a key role in the survival of PL cells against oxidative stress. Induction of miR-93 may increase the sensitivity of PL cells to oxidative stress during chemotherapy to improve therapeutic outcome.

Baranger L, Cuccuini W, Lefebvre C, et al.
Cytogenetics in the management of children and adult acute lymphoblastic leukemia (ALL): an update by the Groupe francophone de cytogénétique hématologique (GFCH).
Ann Biol Clin (Paris). 2016; 74(5):547-560 [PubMed] Related Publications
Cytogenetic analyses (karyotype and, if necessary, appropriate complementary FISH analyses) are mandatory at diagnosis in acute lymphoblastic leukemia (ALL) as their results are taken into account in therapeutic protocols due to their diagnostic and prognostic values. In some cases, karyotype can be completed by other techniques (RT-PCR, RQ-PCR, DNA content, SNP-array, MLPA…) that can be equally or more informative than FISH. Here, we have tempted to establish guidelines concerning karyotype and FISH analyses according to the most recent data of the litterature which is reviewed here, completing the 2008 WHO classification with the recent new cytogenomic entities such as Ph-like ALL and indicating possible therapeutic implications.

Kjeldsen E
Characterization of a novel acquired der(1)del(1)(p13p31)t(1;15)(q42;q15) in a high risk t(12;21)-positive acute lymphoblastic leukemia.
Gene. 2016; 595(1):39-48 [PubMed] Related Publications
The t(12;21)(p13;q22) with ETV6-RUNX1 fusion occurs in 25% of cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL); and is generally associated with favorable prognosis. However, 15-20% of the t(12;21)-positive cases are associated with high-risk disease due to for example slow early responses to therapy. It is well-known that development of overt leukemia in t(12;21)-positive ALL requires secondary chromosomal aberrations although the full spectrum of these cytogenetic alterations is yet unsettled, and also, how they may be associated with disease outcome. This report describes the case of an adolescent male with t(12;21)-positive ALL who displayed a G-banded karyotype initially interpreted as del(1)(p22p13) and del(15)(q15). The patient was treated according to NOPHO standard risk protocol at diagnosis, but had minimal residual disease (MRD) at 6,4% on day 29 as determined by flow cytometric immunophenotyping. Because of MRD level>0.1% he was then assigned as a high risk patient and received intensified chemotherapy accordingly. Further molecular cytogenetic studies and oligo-based aCGH (oaCGH) analysis characterized the acquired complex structural rearrangements on chromosomes 1 and 15, which can be described as der(1)del(1)(p13.1p31.1)t(1;15)(q42;q15) with concurrent deletions at 1q31.2-q31.3, 1q42.12-q43, and 15q15.1-q15.3. The unbalanced complex rearrangements have not been described previously. Extended locus-specific FISH analyses showed that the three deletions were on the same chromosome 1 homologue that was involved in the t(1;15), and that the deletion on chromosome 15 also was on the same chromosome 15 homologue as involved in the t(1;15). Together these findings show the great importance of the combined usage of molecular cytogenetic analyses and oaCGH analysis to enhance characterization of apparently simple G-banded karyotypes, and to provide a more complete spectrum of secondary chromosomal aberrations in high risk t(12;21)-positive BCP-ALLs.

Bhandari P, Ahmad F, Mandava S, Das BR
Association of Genetic Variants in ARID5B, IKZF1 and CEBPE with Risk of Childhood de novo B-Lineage Acute Lymphoblastic Leukemia in India.
Asian Pac J Cancer Prev. 2016; 17(8):3989-95 [PubMed] Related Publications
BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous genetic disease and its etiology remains poorly understood. Recent genome wide association and replication studies have highlighted specic polymorphisms contributing to childhood ALL predispositions mostly in European populations. It is unclear if these observations generalize to other populations with a lower incidence of ALL. The current case-control study evaluated variants in ARID5B (rs7089424, rs10821936), IKZF1 (rs4132601) and CEBPE (rs2239633) genes, which appear most significantly associated with risk of developing childhood B-lineage ALL.
MATERIALS AND METHODS: Using TaqMan assays, genotyping was conducted for 162 de novo B-lineage ALL cases and 150 unrelated healthy controls in India. Appropriate statistical methods were applied.
RESULTS: Genotypic and allelic frequencies differed significantly between cases and controls at IKZF1-rs4132601 (p=0.039, p=0.015) and ARID5B-rs10821936 (p=0.028, p=0.026). Both rs10821936 (p=0.019; OR 0.67; 95% CI=0.47-0.94) and rs4132601 (p=0.018; OR 0.67; 95%CI 0.48-0.94) were associated with reduced disease risk. Moreover, gender- analysis revealed male-specific risk associations for rs10821936 (p=0.041 CT+CC) and rs4132601 (p=0.005 G allele). Further, ARID5B-rs7089424 and CEBPE-rs2239633 showed a trend towards decreased disease risk but without significance (p=0.073; p=0.73).
CONCLUSIONS: Our findings provide the rst evidence that SNPs ARID5B- rs10821936 and IKZF1-rs4132601 are associated with decreased B-lineage ALL susceptibility in Indian children. Understanding the effects of these variants in different ethnic groups is crucial as they may confer different risk of ALL within different populations.

Bahari G, Hashemi M, Naderi M, Taheri M
TET2 Promoter DNA Methylation and Expression in Childhood Acute Lymphoblastic Leukemia.
Asian Pac J Cancer Prev. 2016; 17(8):3959-62 [PubMed] Related Publications
The ten-eleven-translocation-2 (TET2) gene is a novel tumor suppressor gene involved in several hematological malignancies of myeloid and lymphoid origin. Besides loss-of-function mutations and deletions, hypermethylation of the CpG island at the TET2 promoter has been found in human cancers. The TET2 encoded protein regulates DNA methylation. The present study aimed to examine DNA promoter methylation of TET2 in 100 childhood acute lymphoblastic leukemia (ALL) cases and 120 healthy children in southeast Iran. In addition, mRNA expression levels were assessed in 30 new cases of ALL and 32 controls. Our findings indicated that promoter methylation of TET2 significantly increases the risk of ALL (OR=2.60, 95% CI=1.31-5.12, p=0.0060) in comparison with absent methylation. Furthermore, the TET2 gene was significantly downregulated in childhood ALL compared to healthy children (p=0.0235). The results revealed that hypermethylation and downregulation of TET2 gene may play a role in predisposition to childhood ALL. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings.

Akhter A, Mughal MK, Elyamany G, et al.
Multiplexed automated digital quantification of fusion transcripts: comparative study with fluorescent in-situ hybridization (FISH) technique in acute leukemia patients.
Diagn Pathol. 2016; 11(1):89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL.
METHODS: "nCounter® Leukemia fusion gene expression assay" by NanoString was employed to detect various fusion transcripts in a large set samples (n = 94) utilizing RNA from formalin fixed paraffin embedded (FFPE) diagnostic bone marrow biopsy specimens. This series included AL patients with various recurrent translocations (n = 49), normal karyotype (n = 19), or complex karyotype (n = 21), as well as normal bone marrow samples (n = 5). Fusion gene expression data were compared with results obtained by conventional karyotype and FISH technology to determine sensitivity/specificity, as well as positive /negative predictive values.
RESULTS: Junction probes for PML/RARA; RUNX1-RUNX1T1; BCR/ABL1 showed 100 % sensitivity/specificity. A high degree of correlation was noted for MLL/AF4 (85 sensitivity/100 specificity) and TCF3-PBX1 (75 % sensitivity/100 % specificity) probes. CBFB-MYH11 fusion probes showed moderate sensitivity (57 %) but high specificity (100 %). ETV6/RUNX1 displayed discordance between fusion transcript assay and FISH results as well as rare non-specific binding in AL samples with normal or complex cytogenetics.
CONCLUSIONS: Our study presents preliminary data with high correlation between fusion transcript detection by a throughput automated multiplexed platform, compared to conventional karyotype/FISH technique for detection of chromosomal translocations in AL patients. Our preliminary observations, mandates further vast validation studies to explore automated molecular platforms in diagnostic pathology.

Lu Y, Wu D, Wang J, et al.
Identification of Heme Oxygenase-1 as a Novel Predictor of Hematopoietic Stem Cell Transplantation Outcomes in Acute Leukemia.
Cell Physiol Biochem. 2016; 39(4):1495-502 [PubMed] Related Publications
OBJECTIVE: The main aim of this study was to determine the correlation between clinical outcome and heme oxygenase-1 (HO-1) expression before and after hematopoietic stem cell transplantation (HSCT) in acute leukemia.
METHODS: HO-1 mRNA levels in 83 patients were measured using qRT-PCR. In a comparative analysis of HO-1 levels in relation to different post-transplant outcomes, the HO-1 threshold, determined via the receiver operating characteristic (ROC) curve, was effectively used to predict clinical relapse and acute graft-versus-host disease (aGVHD). The correlations among clinical relapse, aGVHD and HO-1 expression were analyzed based on this threshold.
RESULTS: Leukemia risk stratification and relative expression of HO-1 before pretreatment had significant effects on clinical relapse. Leukemia risk stratification, relative expression of HO-1 after HSCT and the interval from diagnosis to transplantation had a significant influence on aGVHD. Both relapse and aGVHD appeared to be associated with relative HO-1 expression. The relative expression rate of HO-1 was 1.131-1.186 before pretreatment, and strongly associated with post-transplantation relapse. The relative expression rate of HO-1 was 1.102-1.144 after transplantation, and closely related to aGVHD. ROC curve analysis revealed high specificity and sensitivity of HO-1 expression in predicting relapse and aGVHD after allo-HSCT.
CONCLUSIONS: HO-1 expression can be effectively used as a predictor of relapse as well as a diagnostic factor of aGVHD after transplantation for allo-HSCT patients with acute leukemia.

Li HF, Meng WT, Jia YQ, et al.
Development-associated immunophenotypes reveal the heterogeneous and individualized early responses of adult B-acute lymphoblastic leukemia.
Medicine (Baltimore). 2016; 95(34):e4128 [PubMed] Related Publications
B cell acute lymphoblastic leukemia (B-ALL) exhibits phenotypes reminiscent of normal stages of B-cell development. As demonstrated by flow cytometry, the immunophenotypes are able to determine the stages of B cell development. Multicolor flow cytometry (MFC) is more accurate at identifying cell populations. In this study, 9-color panels, including CD10, CD19, CD20, CD22, CD34, CD79a, CD179a, and IgM, which are sequentially expressed during B cell development, were designed to detect the leukemia cell subpopulations in adult B-ALL patients. In 23 patients at diagnosis, 192 heterogeneous subpopulations of leukemia cells were detected. Compared with their counterparts at diagnosis and after the 1st course of induction therapy, the responses of the subpopulations were also heterogeneous. In the CD10 population, the residual B cell subpopulations in the BCR/ABL patients were obviously reduced compared to those in the BCR/ABL patients. New subpopulations were detected in 22 of 23 patients and were primarily located in the CD34CD10 populations. Subpopulations of clonal evolution were heterogeneous after induction therapy. Our results suggest that the subpopulations in B-ALL patients should be dynamically monitored by development-associated immunophenotyping before, during, and after induction therapy and to predict the prognosis of the disease.

Kamoda Y, Izumi K, Iioka F, et al.
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Separated into Two Subgroups Associated with Survival by BCR-ABL Fluorescence in situ Hybridization of Segmented Cell Nuclei: Report from a Single Institution.
Acta Haematol. 2016; 136(3):157-66 [PubMed] Related Publications
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) may include the lymphoid blast crisis of chronic myeloid leukemia (CML-BC). We applied fluorescence in situ hybridization (FISH) of the BCR-ABL fusion gene to peripheral blood and/or bone marrow smears to determine whether the fusion was restricted to mononuclear cell nuclei or if segmented cell nuclei representing mature neutrophils also carried the fusion (Seg-FISH). Among 20 patients with Ph+ ALL without a prior diagnosis of CML, 9 were Seg-FISH+ and 11 were Seg-FISH-. Seg-FISH+ cases were characterized by a higher rate of p210-type BCR-ABL transcripts, higher white cell and blast counts, and a higher rate of myeloid and T-lymphoid antigen expression than Seg-FISH- cases, in addition to 'major route' cytogenetic abnormalities associated with CML-BC. Eighteen patients were treated with tyrosine kinase inhibitors (TKIs) either alone or in combination with multiagent chemotherapy, and 7 underwent allogeneic hematopoietic stem cell transplantation. Progression-free and overall survivals were greater in the Seg-FISH+ group than in the Seg-FISH- group. These results suggest that the Seg-FISH+ group represents lymphoid CML-BC that occurs de novo, while the Seg-FISH- represents Ph+ ALL in the strict sense, and the two groups are associated with survival when treated with TKIs or TKI-combined therapy.

Zeng MN, Ma WL, Zheng WL
[Bioinformatics analysis of microRNA comprehensive regulatory network in B- cell acute lymphoblastic leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(7):585-90 [PubMed] Related Publications
OBJECTIVE: To reveal the involvement of molecules in the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL) by bioinformatics analyses.
METHODS: The microarray data of B-ALL were downloaded from the Gene Expression Omnibus (GEO) database and Qlucore Omics Explorer software was used to screen differentially expressed miRNA. Based on the differentially expressed miRNAs, we predicted the target genes, long non-coding RNAs (lncRNA) and transcription factors (TFs). Then we constructed the miRNAs-centered comprehensive regulatory network. In addition, we performed functional enrichment analysis to analyze the functions of target genes.
RESULTS: Of all the 15 differentially expressed miRNAs, 7 miRNAs were of overexpression, 8 miRNAs underexpressed. From the miRNAs comprehensive regulatory network, we found that hsa-miR-486-3p and hsa-miR-126 regulated a large number of target genes, hsa-miR-126 including target genes MYC. The hsa-miR-29a, hsa-miR-130a and hsa-miR-181c regu- lated a lot of lncRNAs containing X-inactive-specific transcript (XIST). The hsa-miR-181a-2, hsa-miR- 181b-2 and hsa-miR-663 were regulated by a host of TFs including caudal- related homeobox transcription fact2 (CDX2). Additionally, the target genes of has-miR-126 were enriched in Wnt pathways.
CONCLUSIONS: The expression of hsa-miR-29a , hsa-miR-126 and has-miR-181 family were significantly different in B-ALL. Target gene of MYC, TFs of CDX2 and lncRNA of XIST may play important roles in the development of B-ALL, serving as a potential therapeutic target.

Hossain A, Gupta K, Mener A, Tabbara I
Case of CML lymphoid blast crisis presenting as bilateral breast masses.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts.

Yoshida K
Genetic abnormalities associated with the relapse of childhood leukemia.
Rinsho Ketsueki. 2016; 57(7):919-24 [PubMed] Related Publications
Acute leukemia, especially acute lymphoblastic leukemia, is the most common tumor in childhood. Survival in pediatric acute leukemia cases has improved significantly, but once a relapse occurs, the long-term survival rates decrease markedly. Recently, SNP array and next-generation sequencing have revealed the relapse mechanism of pediatric leukemia and genetic alterations which drive leukemia recurrence.

Moriyama T
Familial acute lymphoblastic leukemia.
Rinsho Ketsueki. 2016; 57(7):900-9 [PubMed] Related Publications
Somatically acquired genomic alterations have been recognized as key hallmarks inducing acute lymphoblastic leukemia (ALL), though recent knowledge acquired from genome-wide association study (GWAS) has revealed that inherited genetic variations (germline) are associated with ALL susceptibility as well as disease onset. The proportion of ALL cases attributable to an inherited genetic predisposition has been recognized as being much higher in clinical practice than previously thought since familial cases with hematopoietic transcriptional factors (PAX5 and ETV6) were reported. Considering the characteristics related to inherited variants, issues associated with these variants persist from childhood throughout the patient's entire life, and specific approaches to both familial ALL cases and carriers with inherited variants are thus urgently needed. This review focuses on familial ALL caused by the two aforementioned transcriptional factors (PAX5 and ETV6).

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