CML - Molecular Biology


Chronic myelogenous leukemia (CML) is characterised by the Philadelphia (Ph) chromosome which is seen in over 95% of patients. The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, this fuses the ABL1 from chromosome 9 to the BCR gene on chromosome 22. The median age of patients with Ph+ CML is 67 years of age, it can occasionally occur in children (2-3% of all childhood leukaemias).

See also: Chronic Myeloid Leukemia (CML) - clinical resources (24)

Literature Analysis

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

  • Antineoplastic Agents
  • siRNA
  • ASXL1
  • Messenger RNA
  • Reactive Oxygen Species
  • Protein Transport
  • Piperazines
  • Signal Transduction
  • Proto-Oncogene Proteins c-bcr
  • eIF-2 Kinase
  • Treatment Refusal
  • PRDM16
  • Single Nucleotide Polymorphism
  • Young Adult
  • DNA Sequence Analysis
  • Polymerase Chain Reaction
  • EVI1
  • Drug Resistance
  • Imatinib Mesylate
  • Pyridazines
  • Treatment Failure
  • NUP98
  • Withholding Treatment
  • Remission Induction
  • Reproducibility of Results
  • TET2
  • CRKL
  • Protein-Tyrosine Kinases
  • Chronic Myelogenous Leukemia
  • Mutation
  • Tumor Suppressor Protein p14ARF
  • Reference Standards
  • Benzamides
  • Genes, myb
  • Sequence Deletion
  • Protein Structure, Tertiary
  • Stem Cells
  • PDCD5
  • src Homology Domains
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Two-Hybrid System Techniques
  • Survival Rate
  • Telomerase
  • BCR
  • JUNB
  • Fusion Proteins, bcr-abl
  • HOXA9
  • Tumor Suppressor Proteins
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (66)

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 Chronic Myeloid Leukaemia
-BCR and Chronic Myelogenous Leukemia
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Chronic Myelogenous Leukemia
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Chronic Myelogenous Leukemia
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Chronic Myelogenous Leukemia
CD34 1q32 -CD34 and Chronic Myelogenous Leukemia
CD33 19q13.41 p67, SIGLEC3, SIGLEC-3 -CD33 and Chronic Myelogenous Leukemia
TET2 4q24 MDS, KIAA1546 -TET2 and Chronic Myelomonocytic Leukemia
HOXA9 7p15.2 HOX1, ABD-B, HOX1G, HOX1.7 -HOXA9 and Chronic Myelogenous Leukemia
-t(7;11)(p15;p15) in Chronic Myelogenous Leukaemia
CRKL 22q11.21 -CRKL and Chronic Myelogenous Leukemia
MECOM 3q26.2 EVI1, MDS1, PRDM3, MDS1-EVI1, AML1-EVI-1 -MECOM and Chronic Myelogenous Leukemia
NUP98 11p15.4 ADIR2, NUP96, NUP196 -NUP98 and Chronic Myelogenous Leukemia
-t(7;11)(p15;p15) in Chronic Myelogenous Leukaemia
GALE 1p36-p35 SDR1E1 -GALE and Chronic Myelogenous Leukemia
LYN 8q13 JTK8, p53Lyn, p56Lyn -LYN and Chronic Myelogenous Leukemia
JUNB 19p13.2 AP-1 -JUNB and Chronic Myelogenous Leukemia
GRB2 17q24-q25 ASH, Grb3-3, MST084, NCKAP2, MSTP084, EGFRBP-GRB2 -GRB2 and Chronic Myelogenous Leukemia
ELN 7q11.23 WS, WBS, SVAS -ELN and Chronic Myelogenous Leukemia
WARS 14q32.31 IFI53, IFP53, GAMMA-2 -WARS and Chronic Myelogenous Leukemia
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Chronic Myelogenous Leukemia
ASXL1 20q11 MDS, BOPS -ASXL1 and Chronic Myelogenous Leukemia
MYB 6q22-q23 efg, Cmyb, c-myb, c-myb_CDS -Genes, myb and Chronic Myelogenous Leukemia
CD36 7q11.2 FAT, GP4, GP3B, GPIV, CHDS7, PASIV, SCARB3, BDPLT10 -CD36 and Chronic Myelogenous Leukemia
CD83 6p23 BL11, HB15 -CD83 and Chronic Myelogenous Leukemia
MDS1 3q26 PRDM3, MDS1-EVI1 -MDS1 and Chronic Myelogenous Leukemia
G6PD Xq28 G6PD1 -G6PD and Chronic Myelogenous Leukemia
PCM1 8p22-p21.3 PTC4, RET/PCM-1 -PCM1 and Chronic Myelogenous Leukemia
IRF8 16q24.1 ICSBP, IRF-8, ICSBP1, IMD32A, IMD32B, H-ICSBP -IRF8 and Chronic Myelogenous Leukemia
GAB2 11q14.1 -GAB2 and Chronic Myelogenous Leukemia
GUSB 7q21.11 BG, MPS7 -GUSB and Chronic Myelogenous Leukemia
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 Expression in Chronic Myeloid Leukemia
POU2F1 1q24.2 OCT1, OTF1, oct-1B -POU2F1 and Chronic Myelogenous Leukemia
HCK 20q11-q12 JTK9, p59Hck, p61Hck -HCK and Chronic Myelogenous Leukemia
SALL4 20q13.2 DRRS, HSAL4, ZNF797, dJ1112F19.1 -SALL4 and Chronic Myelogenous Leukemia
PRDM16 1p36.23-p33 MEL1, LVNC8, PFM13, CMD1LL -PRDM16 and Chronic Myelogenous Leukemia
TRA 14q11.2 IMD7, TCRA, TCRD, TRA@, TRAC -TRA and Chronic Myelogenous Leukemia
CD59 11p13 1F5, EJ16, EJ30, EL32, G344, MIN1, MIN2, MIN3, MIRL, HRF20, MACIF, MEM43, MIC11, MSK21, 16.3A5, HRF-20, MAC-IP, p18-20 -CD59 and Chronic Myelogenous Leukemia
BACH2 6q15 BTBD25 -BACH2 and Chronic Myelogenous Leukemia
ATG7 3p25.3 GSA7, APG7L, APG7-LIKE -ATG7 and Chronic Myelogenous Leukemia
CD55 1q32 CR, TC, DAF, CROM -CD55 and Chronic Myelogenous Leukemia
IRF2 4q34.1-q35.1 IRF-2 -IRF2 and Chronic Myelogenous Leukemia
U2AF1 21q22.3 RN, FP793, U2AF35, U2AFBP, RNU2AF1 -U2AF1 and Chronic Myelogenous Leukemia
PDCD5 19q13.11 TFAR19 -PDCD5 and Chronic Myelogenous Leukemia
SLC9A1 1p36.1-p35 APNH, NHE1, LIKNS, NHE-1, PPP1R143 -SLC9A1 and Chronic Myelogenous Leukemia
ZRSR2 Xp22.1 URP, ZC3H22, U2AF1L2, U2AF1RS2, U2AF1-RS2 -ZRSR2 and Chronic Myelogenous Leukemia
HDGF 1q23.1 HMG1L2 -HDGF and Chronic Myelogenous Leukemia
ARHGAP26 5q31 GRAF, GRAF1, OPHN1L, OPHN1L1 -ARHGAP26 and Chronic Myelogenous Leukemia
RIN1 11q13.2 -RIN1 and Chronic Myelogenous Leukemia
MSI2 17q22 MSI2H -MSI2 and Chronic Myelogenous Leukemia
ABI2 2q33 ABI-2, ABI2B, AIP-1, AblBP3, argBP1, SSH3BP2, argBPIA, argBPIB -ABI2 and Chronic Myelogenous Leukemia
SRSF2 17q25.1 SC35, PR264, SC-35, SFRS2, SFRS2A, SRp30b -SRSF2 and Chronic Myelogenous Leukemia
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Chronic Myelogenous Leukemia
MAFG 17q25.3 hMAF -MAFG and Chronic Myelogenous Leukemia
RNF217-AS1 6q22.33 STL -STL and Chronic Myelogenous Leukemia
ENDOU 12q13.1 P11, PP11, PRSS26 -ENDOU and Chronic Myelogenous Leukemia
CBLB 3q13.11 Cbl-b, RNF56, Nbla00127 -CBLB and Chronic Myelogenous Leukemia
PDCD1LG2 9p24.2 B7DC, Btdc, PDL2, CD273, PD-L2, PDCD1L2, bA574F11.2 -PDCD1LG2 and Chronic Myelogenous Leukemia
CBLC 19q13.2 CBL-3, RNF57, CBL-SL -CBLC and Chronic Myelogenous Leukemia
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Chronic Myelogenous Leukemia
ZNF384 12p12 NP, CIZ, NMP4, CAGH1, ERDA2, TNRC1, CAGH1A -ZNF384 and Chronic Myelogenous Leukemia
HLA-DPB1 6p21.3 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Chronic Myelogenous Leukemia
FGFR1OP 6q27 FOP -FGFR1OP and Chronic Myelogenous Leukemia
ESPL1 12q ESP1, SEPA -ESPL1 and Chronic Myelogenous Leukemia
RPN1 3q21.3 OST1, RBPH1 -RPN1 and Chronic Myelogenous Leukemia
HOXC11 12q13.3 HOX3H -HOXC11 and Chronic Myelogenous Leukemia
PLCD1 3p22-p21.3 NDNC3, PLC-III -PLCD1 and Chronic Myelogenous Leukemia
PRTN3 19p13.3 MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA -PRTN3 and Chronic Myelogenous Leukemia
ABL1 9q34.1 ABL, JTK7, p150, c-ABL, v-abl, c-ABL1, bcr/abl Translocation
-BCR-ABL Translocation in Chronic Myeloid Leukaemia

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

Latest Research Publications

Lu Y, Li Y, Chai X, et al.
Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia.
Gene. 2017; 607:41-46 [PubMed] Related Publications
Aberrant expression of long noncoding RNA (lncRNA) HULC is associated with various human cancers. However, the role of HULC in chronic myeloid leukemia (CML) is unknown. In this study, we found that HULC was remarkably overexpressed in both leukemia cell lines and primary hematopoietic cells derived from CML patients. The increase in HULC expression was positively correlated with clinical stages in CML. Moreover, the knockdown of HULC significantly inhibited CML cell proliferation and induced apoptosis by repressing c-Myc and Bcl-2. Furthermore, inhibition of HULC enhanced imatinib-induced apoptosis of CML cells. Further experiments demonstrated that HULC silencing markedly suppressed the phosphorylation of PI3K and AKT, indicating that enhancement of imatinib-induced apoptosis by HULC inhibition is related with the reduction of c-Myc expression and inhibition of PI3K/Akt pathway activity. Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge. Taken together, these results reveal that HULC promotes oncogenesis in CML and suggest a potential strategy for the CML treatment.

Ahmad HM, Muiwo P, Muthuswami R, Bhattacharya A
FosB regulates expression of miR-22 during PMA induced differentiation of K562 cells to megakaryocytes.
Biochimie. 2017; 133:1-6 [PubMed] Related Publications
Expression of many miRNAs is altered in different cancers and these changes are thought to play a key role in formation and progression of cancer. In chronic myelogenous leukemia (CML) a number of miRNAs are known to be down regulated as compared to normal cells. In this report we have investigated the mechanism of this down regulation by using PMA induced differentiation of CML cell line K562 to megakaryocytes as an experimental system. On treatment with PMA, expression of many down regulated miRNAs including miR-22 is induced. PMA also induces expression of several transcription factors, including FosB, EGR1 and EGR2. Our results using a number of approaches, such as promoter reporter assay, FosB knock down and Chip assay, suggest that the expression of miR-22 is regulated transcriptionally by FosB.

Farhadi E, Zaker F, Safa M, Rezvani MR
miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes.
Tumour Biol. 2016; 37(10):14117-14128 [PubMed] Related Publications
Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

Pan J, Tan YH, Zhao JX, et al.
[Discovery of a novel spliceosome of ABL gene (ABL(Δexon7+35INS)) and its association with TKIs resistance in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(6):503-6 [PubMed] Related Publications
OBJECTIVE: To explore whether the ABL(Δexon7) and ABL(35INS) spliceosome contributed to TKIs resistance.
METHODS: Screening ABL(Δexon7) and ABL(35INS) in 74 normal people and 76 CML patients (53 patients in remission and 23 patients with TKIs resistance) by using polyacrylamide gel electrophoresis combined with cloning sequencing.
RESULTS: A novel spliceosome ABL(Δexon7+ 35INS) (ABL(Δexon7) and ABL(3)5INS existed at the same time) was identified and the mutation was detected in 8 (10.8%) of 74 normal people, 4 (7.5%) of 53 remission patients and 2 (8.7%) of 23 resistant patients. While 47 (63.5%) cases expressed ABL(Δexon7) and 8 (10.8% ) cases expressed ABL(35INS) in 74 healthy people, 30 (56.6%) cases expressed ABL(Δexon7) and 5 (9.4% ) cases expressed ABL(35INS) in 53 remission patients, 12 (52.2%) cases expressed ABL(Δexon7) and 3(13.0%) cases expressed ABL(35INS) in 23 resistant patients. Three kinds of spliceosome in all groups had no statistical difference.
CONCLUSION: ABL(Δexon7+ 35INS), ABL(Δexon7) and ABL(35INS) may be not uncommon in ABL gene and were unrelated to resistance in CML with TKIs treatment. ABL(35INS) were often accompanying with exon 7 deletion.

Ikonnikova AY, Yatsenko YE, Kremenetskaya OS, et al.
[Detection of BCR-ABL gene mutations in chronic myeloid leukemia using biochips].
Mol Biol (Mosk). 2016 May-Jun; 50(3):474-9 [PubMed] Related Publications
A biochip-based method was developed to identify the BCR-ABL mutations that affect the thyrosine kinase domain and determine resistance to targeted therapy with thyrosine kinase inhibitors. The method is based on RT-PCR followed by allele-specific hybridization on a biochip with immobilized oligonucleotide probes. The biochip addresses 11 mutations, which are responsible for up to 85% of imatinib resistance cases. A method to decect the clinically significant mutation T315I was designed on the basis of LNA-clamped PCR and proved highly sensitive, detecting the mutation in clinical samples with a leukemic cell content of 5% or higher. The method was validated using clinical samples from chronic myeloid leukemia (CML) patients with acquired resistance to imatinib. The results of hybridization on biochip were verified by Sanger sequencing.

Ji M, Hur M, Kim HN, et al.
Presence of Additional Cytogenetic Abnormality of t(1;15) at Diagnosis of Chronic Myelogenous Leukemia-Chronic Phase.
Ann Clin Lab Sci. 2016; 46(3):308-11 [PubMed] Related Publications
At diagnosis, fewer than 10% of chronic myelogenous leukemia (CML) patients have additional cytogenetic abnormalities (ACAs), which are frequently found in transformation to blast crisis. We report a case of CML-chronic phase (CML-CP) that showed t(1;15) at diagnosis. A 64-year-old man presented with sustained leukocytosis and thrombocytosis. His bone marrow (BM) was hypercellular with 2.5% blasts and BCR-ABL1 rearrangement. The karyotype in the BM was 46,XY,t(1;15)(q32;p13),t(9;22)(q34;q11.2)[20], while the karyotype in the peripheral blood was 46,XY[20]. This is the first report on the presence of t(1;15) at diagnosis of CML-CP, and its clinical significance remains unclear.

Al-Achkar W, Moassass F, Youssef N, Wafa A
Correlation of p210 BCR-ABL transcript variants with clinical, parameters and disease outcome in 45 chronic myeloid leukemia patients.
J BUON. 2016 Mar-Apr; 21(2):444-9 [PubMed] Related Publications
PURPOSE: The aim of this study was to search the BCR/ABL 1 fusion gene in 45 chronic myeloid leukemia (CML) Syrian patients using nested reverse transcription polymerase chain reaction (RT-PCR) and compare our results with those of conventional cytogenetics and molecular cytogenetics methods.
METHODS: 45 bone marrow or peripheral blood samples from untreated CML patients in chronic phase (CP) were obtained at diagnosis, and analyzed by nested RT-PCR, conventional cytogenetics and molecular cyto-genetics methods.
RESULTS: 45 patients examined were positive for some type of BCR/ABL1 fusion gene rearrangement. Out of 45 studied CML patients, 23 (51.1%) expressed b3a2 fusion transcript, 21 (46.7%) b2a2 transcript, and 1 (2.2%) a rare b2a3 transcript. No patient co-expressed both b3a2/b2a2 types.
CONCLUSIONS: The distribution BCR-ABL1 transcript types found in Syria were similar to that of Indian Far-Eastern, African or European populations and the M-BCR rearrangement types were not dependent on white blood count (WBC), platelet count, hemoglobin level or gender of the patients. Overall, we could show that patients with b3a2 rearrangements were younger than patients with b2a2 transcripts, thus our young patients may have a worse prognosis.

Kang ZJ, Liu YF, Xu LZ, et al.
The Philadelphia chromosome in leukemogenesis.
Chin J Cancer. 2016; 35:48 [PubMed] Free Access to Full Article Related Publications
The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase (BCR-ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary. Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis.

Gutiérrez-Malacatt H, Ayala-Sanchez M, Aquino-Ortega X, et al.
The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women.
Asian Pac J Cancer Prev. 2016; 17(4):2265-70 [PubMed] Related Publications
BACKGROUND: Chronic myeloid leukemia (CML) is one of the most frequent hematopoietic malignancies in the elderly population; however, knowledge is limited regarding the genetic factors associated with increased risk for CML. Polymorphisms affecting microRNA (miRNA) biogenesis or mRNA:miRNA interactions are important risk factors in the development of different types of cancer. Thus, we carried out a case-control study to test the association with CML susceptibility of gene variants located in the miRNA machinery genes AGO1 (rs636832) and GEMIN4 (rs2740348), as well as in the miRNA binding sites of the genes BRCA1 (rs799917) and KRAS (rs61764370).
MATERIALS AND METHODS: We determined the genotype of 781 Mexican-Mestizo individuals (469 healthy subjects and 312 CML cases) for the four polymorphisms using TaqMan probes to test the association with CML susceptibility.
RESULTS: We found a borderline association of the minor homozygote genotype of the KRAS_rs61764370 polymorphism with an increased risk for CML susceptibility (P = 0.06). After gender stratification, this association was significant only for women (odds ratio [OR] = 13.41, P = 0.04). The distribution of the allelic and genotypic frequencies of the four studied SNPs was neither associated with advanced phases of CML nor treatment response.
CONCLUSIONS: To the best of our knowledge, this study is the first to show a significant association of the KRAS_rs61764370 SNP with CML. To further determine such an association of with CML susceptibility, our results must be replicated in different ethnic groups.

Wang J, Zhang Y, Zhou J, et al.
[Clinical observation of chromosomal abnormalities in Ph negative cells of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(5):412-6 [PubMed] Related Publications
OBJECTIVE: To observe the clinical features, characteristics and outcomes of chromosomal abnormalities in Philadelphia negative cells (Ph(-)CA) of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI), and provide the evidence for clinical treatment.
METHODS: We collected and analyzed the clinical and laboratory data of 8 CML patients treated in the affiliated Tumor Hospital of Zhengzhou University from September 2011 to July 2015 and Ph(-)CA occurred after TKI therapy. Karyotypes and BCR-ABL fusion genes were analyzed by R-banding and real-time quantitative polymerase chain reaction (RT-PCR), respectively.
RESULTS: 6 cases were male and 2 cases were female, with a median age of 51 (31-75) years old. 6 patients had low Sokal risk scores and 2 had intermediate scores. 4 cases of Ph(-) CA occurred with imatinib, 1 case with dasatinib and 3 cases with nilotinib. The median duration of Ph(-) CA appearance was 12.0 (1.7-34.5) months since taking TKI. Chromosomal abnormality +8 was the most common type in Ph(-)CA, which accounted for 50.0%, followed by -7 (25.0%). When found Ph(-)CA, all patients had complete hematologic response (CHR), but none got main molecular response (MMR). The Ph(-)CA had gone in 7 cases at the end of follow-up and the median duration was 6.2 (2.5-31.5) months. After Ph(-) CA disappeared, 1 patient obtained MMR and 2 cases achieved complete molecular response (CMR), but Ph(+) clone recurred in 1 case.
CONCLUSION: Ph(-)CA can be found in CML patients treated with imatinib, dasatinib and nilotinib, and +8 is the most common Ph(-)CA. So detection of karyotype is significant during treatment. Although most Ph(-)CA can disappear, -7/7q- or other complex karyotypes should be monitored closely.

Cordeiro M, Giestas L, Lima JC, Baptista PM
BioCode gold-nanobeacon for the detection of fusion transcripts causing chronic myeloid leukemia.
J Nanobiotechnology. 2016; 14(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gold-nanobeacons (Au-nanobeacons) have proven to be versatile systems for molecular diagnostics and therapeutic actuators. Here, we present the development and characterization of two gold nanobeacons combined with Förster resonance energy transfer (FRET) based spectral codification for dual mode sequence discrimination. This is the combination of two powerful technologies onto a single nanosystem.
RESULTS: We proved this concept to detect the most common fusion sequences associated with the development of chronic myeloid leukemia, e13a2 and e14a2. The detection is based on spectral shift of the donor signal to the acceptor, which allows for corroboration of the hybridization event. The Au-nanobeacon acts as scaffold for detection of the target in a homogenous format whose output capability (i.e. additional layer of information) is potentiated via the spectral codification strategy.
CONCLUSIONS: The spectral coded Au-nanobeacons permit the detection of each of the pathogenic fusion sequences, with high specificity towards partial complementary sequences. The proposed BioCode Au-nanobeacon concept provides for a nanoplatform for molecular recognition suitable for cancer diagnostics.

Kurosawa S, Doki N, Kaito S, et al.
[Chronic myelogenous leukemia initially presenting with multiple subcutaneous tumors due to extramedullary hematopoiesis].
Rinsho Ketsueki. 2016; 57(4):461-6 [PubMed] Related Publications
A 53-year-old woman was admitted with right upper-extremity pain and multiple subcutaneous masses. Bone marrow aspirate showed hypercellular marrow with increased myeloid components at all stages of maturation. Cytogenetic analysis of the bone marrow revealed 100% Philadelphia chromosome positivity along with BCR/ABL gene rearrangement, as demonstrated by polymerase chain reaction (PCR). A diagnosis of chronic phase of chronic myeloid leukemia (CML) was therefore made. Biopsy of one of the subcutaneous masses showed proliferation of granulocytes in various stages of differentiation. There were also erythroid cells and megakaryocytes, without p53 and CD34-positive blasts. These results suggested that the subcutaneous masses had developed from extramedullary hematopoiesis, not blastomas. The patient was administered dasatinib (DA) 140 mg, combined with radiation therapy for pain and peripheral neuropathy from the right axial extramedullary tumor. The patient showed complete hematological remission and the subcutaneous masses had disappeared 1 month after starting administration of DA. Because the patient did not achieve a cytogenetic response, the tyrosine kinase inhibitor nilotinib was administered. She will undergo allogeneic stem cell transplantation in the near future. Extramedullary hematopoiesis in the early stages of CML is uncommon. Our case emphasizes the need to elucidate the pathogenesis of extramedullary hematopoiesis in the early stages of CML.

Ohyashiki K, Umezu T, Katagiri S, et al.
Downregulation of Plasma miR-215 in Chronic Myeloid Leukemia Patients with Successful Discontinuation of Imatinib.
Int J Mol Sci. 2016; 17(4):570 [PubMed] Free Access to Full Article Related Publications
Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients who were able to discontinue IM. We first screened candidate miRNAs in unselected STOP-IM patients, who had sustained UMRD after discontinuing IM for more than six months, in comparison with healthy volunteers, by using a TaqMan low-density array for plasma or exosomes. Exosomal miR-215 and plasma miR-215 were downregulated in the STOP-IM group compared to the control, indicating that the biological relevance of the plasma miR-215 level is equivalent to that of the exosomal level. Next, we performed real-time quantitative RT-PCR in 20 STOP-IM patients, 32 patients with UMRD on continued IM therapy (IM group) and 28 healthy volunteers. The plasma miRNA-215 level was significantly downregulated in the STOP-IM group (p < 0.0001); we determined the cut-off level and divided the IM group patients into two groups according to whether the plasma miR-215 was downregulated or not. The IM group patients with a low plasma miR-215 level had a significantly higher total IM intake, compared to the patients with elevated miR-215 levels (p = 0.0229). Functional annotation of miR-215 target genes estimated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools involved cell cycle, mitosis, DNA repair and cell cycle checkpoint. Our study suggests a possible role of miR-215 in successful IM discontinuation.

Pineda G, Lennon KM, Delos Santos NP, et al.
Tracking of Normal and Malignant Progenitor Cell Cycle Transit in a Defined Niche.
Sci Rep. 2016; 6:23885 [PubMed] Free Access to Full Article Related Publications
While implicated in therapeutic resistance, malignant progenitor cell cycle kinetics have been difficult to quantify in real-time. We developed an efficient lentiviral bicistronic fluorescent, ubiquitination-based cell cycle indicator reporter (Fucci2BL) to image live single progenitors on a defined niche coupled with cell cycle gene expression analysis. We have identified key differences in cell cycle regulatory gene expression and transit times between normal and chronic myeloid leukemia progenitors that may inform cancer stem cell eradication strategies.

Yi YJ, Jia XH, Wang JY, et al.
Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P-gp and MRP-1.
Int J Mol Med. 2016; 37(5):1405-11 [PubMed] Related Publications
Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.

Eyüpoğlu D, Bozkurt S, Haznedaroğlu İ, et al.
The Impact of Variant Philadelphia Chromosome Translocations on the Clinical Course of Chronic Myeloid Leukemia.
Turk J Haematol. 2016; 33(1):60-5 [PubMed] Free Access to Full Article Related Publications
Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22) with the formation of Philadelphia (Ph) chromosome. Sometimes, the Ph translocation is generated by variant rearrangements. The prognostic impact of the variant translocations is still controversial. Among the 180 patients with Ph-positive CML who were treated in Hacettepe University Faculty of Medicine Division of Hematology, variant translocations were detected, and retrospectively clinical and prognostic features were described. Also we performed a comprehensive literature review on the prognosis of such variant cases before and after tyrosine kinase inhibitor era. Five patients (2.7%) had variant Ph chromosomes, involved in the rearrangements were chromosomes 2 (2 cases), 11, 14 and 15. Patients were treated with imatinib or dasatinib. All patients reached a stable major molecular response suggesting a prognosis not worse than standard translocation individuals. Our present data were compatible with the data of previous studies indicating no difference in the prognosis between standard and variant translocations in tyrosine kinase inhibitors era of CML.

Wang J, Zhang Y, Zu Y, et al.
[Characteristics and clinical outcome of T315I mutation in Philadelphia chromosome-positive acute lymphoblastic leukemia and chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(2):110-4 [PubMed] Related Publications
OBJECTIVE: To investigate the characteristics and clinical outcome of T315I mutation in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) and chronic myeloid leukemia (CML).
METHODS: The clinical data of 118 tyrosine kinase inhibitors (TKIs) resistant Ph(+) ALL and CML cases who were detected ABL kinase domain mutation in Affiliated Tumor Hospital of Zhengzhou University from March 2014 to June 2015 were collected. Karyotypes and BCR-ABL fusion gene were analyzed respectively by R-banding, real-time quantitative polymerase chain reaction (PCR). Total RNA was extracted by TRIzol reagent and ABL kinase domain mutation was detected by direct sequencing.
RESULTS: In 23 TKIs resistant Ph(+) ALL and 95 CML cases, the rate of ABL kinase domain mutation was 60.9% (14/23) and 41.1% (39/95), respectively, and the rate of T315I mutation was respectively 34. 8% vs 5.3%, the difference was significant (χ(2)=13.586, P<0.01). The rate of mutations in chronic phase/accelerate phase /blast crisis CML patients was 38.8% (19/49), 47.1% (8/17) and 41.4% (12/29), respectively, and there was no significant difference (χ(2)=0.360, P=0.835). In Ph (+) ALL and CML patients, the median time from the beginning of TKI therapy to appearance of T315I mutation was 10 months and 19 months, the median time from the appearance of T315I to death/deadline was 2 months and 3 months, the median time of persistent hematologic response was 10 months and 16 months and the median time of overall survival (OS) was 13 months and 42 months.
CONCLUSION: T315I mutation was more easily occurred in Ph(+) ALL than CML, but two diseases are similar in the median time from the beginning of TKI therapy to appearance of T315I, the median time of persistent hematologic response and OS.

Zheng Q, Cao J, Hamad N, et al.
Single nucleotide polymorphisms in apoptosis pathway are associated with response to imatinib therapy in chronic myeloid leukemia.
J Transl Med. 2016; 14:82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The mechanism of action of imatinib is known to involve the Fas-mediated apoptosis pathway. Consequently inter-individual variations in this apoptosis pathway might be associated with imatinib response or resistance.
METHODS: This study attempted to focus on eight genotypes in the apoptosis pathway including FAS (rs1800682, rs2229521, rs2234767 and rs2234978), FASLG (rs763110), CASP10 (rs13006529), and APAF1 (rs1439123, rs2288713) and analyzed their association with treatment outcomes including molecular response with 4.5 log reduction (MR4.5), following imatinib therapy in 187 Korean CML patients.
RESULTS: The GG/GA genotype in FAS (rs2234767) showed a higher rate of MR4.5 than the AA genotype (at 5 years 59.7 vs 37.4 %, p = 0.013). Using a bootstrap procedure for internal validation we confirmed that FAS (rs2234767) correlates with MR4.5 (p = 0.050). Multivariate analysis confirmed that the FAS genotype (rs2234767) is an independent surrogate for MR4.5 (p = 0.019, HR 0.43, 95 % CI [0.22-0.87]).
CONCLUSIONS: The Fas/FasL signaling pathway may represent the major pathway that mediates apoptosis in CML treated with imatinib. SNP markers in the apoptosis pathway including FAS genotype (rs2234767) can be potential surrogates for predicting deeper molecular response after imatinib therapy.

Gorre M, Mohandas PE, Kagita S, et al.
Significance of ATM Gene Polymorphisms in Chronic Myeloid Leukemia - a Case Control Study from India.
Asian Pac J Cancer Prev. 2016; 17(2):815-21 [PubMed] Related Publications
BACKGROUND: Development of chronic myeloid leukemia (CML) involves formation of double strand breaks (DSBs) which are initially sensed by the ataxia telangiectasia mutated (ATM) signal kinase to induce a DNA damage response (DDR). Mutations or single nucleotide polymorphisms in ATM gene are known to influence the signaling capacity resulting in susceptibility to certain genetic diseases such as cancers.
MATERIALS AND METHODS: In the present study, we have analyzed -5144A>T (rs228589) and C4138T (rs3092856) polymorphisms of theATM gene through polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 925 subjects (476 CML cases and 449 controls).
RESULTS: The A allele of -5144A>T polymorphism and T allele of C4138T polymorphism which were known to be influencing ATM signaling capacity are significantly associated with enhanced risk for CML independently and also in combination (evident from the haplotype and diplotype analyses). Significant elevation in the frequencies of both the risk alleles among high risk groups under European Treatment and Outcome Study (EUTOS) score suggests the possible role of these polymorphisms in predicting the prognosis of CML patients.
CONCLUSIONS: This study provides the first evidence of association of functional ATM gene polymorphisms with the increased risk of CML development as well as progression.

Limsuwanachot N, Siriboonpiputtana T, Karntisawiwat K, et al.
Multiplex RT-PCR Assay for Detection of Common Fusion Transcripts in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Cases.
Asian Pac J Cancer Prev. 2016; 17(2):677-84 [PubMed] Related Publications
BACKGROUND: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease which requires a risk-stratified approach for appropriate treatment. Specific chromosomal translocations within leukemic blasts are important prognostic factors that allow identification of relevant subgroups. In this study, we developed a multiplex RT-PCR assay for detection of the 4 most frequent translocations in ALL (BCR-ABL, TEL-AML1, MLL-AF4, and E2A- PBX1).
MATERIALS AND METHODS: A total of 214 diagnosed ALL samples from both adult and pediatric ALL and 14 cases of CML patients (154 bone marrow and 74 peripheral blood samples) were assessed for specific chromosomal translocations by cytogenetic and multiplex RT-PCR assays.
RESULTS: The results showed that 46 cases of ALL and CML (20.2%) contained the fusion transcripts. Within the positive ALL patients, the most prevalent cryptic translocation observed was mBCR-ABL (p190) at 8.41%. In addition, other genetic rearrangements detected by the multiplex PCR were 4.21% TEL-AML1 and 2.34% E2A-PBX1, whereas MLL-AF4 exhibited negative results in all tested samples. Moreover, MBCR-ABL was detected in all 14 CML samples. In 16 samples of normal karyotype ALL (n=9), ALL with no cytogentic result (n=4) and CML with no Philadelphia chromosome (n=3), fusion transcripts were detected.
CONCLUSIONS: Multiplex RT-PCR provides a rapid, simple and highly sensitive method to detect fusion transcripts for prognostic and risk stratification of ALL and CML patients.

Meng Z, Li YH
[One of the Mechanisms in Blastic Transformation of Chronic Myeloid Leukemia: Epigenetics Abnormality--Review].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(1):250-3 [PubMed] Related Publications
Chronic myeloid leukemia is a myeloproliferative disorder characterized by excessive cloning of bone marrow multipotent stem cells. According to the disease course, the CML may be divided into chronic phase (CP), accelerated phase (AP) and blastic phase (BP). At present, the molecular mechanisms of acute transformation of CML has not been fully understood. The recent studies have shown that the epigenetics is one of mechanisms in blastic transformation of CML, including three molecular mechanisms such as DNA modification, histone modifications and RNA-related dysregulation. The molecular mechanisms for epigenetics leading to the transformation of CML are discussed in this review.

Wu DH, Yang J, Yang L, et al.
[Methylation of miR-378 in Chronic Myeloid Leukemia].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(1):61-5 [PubMed] Related Publications
OBJECTIVE: To investigate the methylation status of miR-378 promoter in chronic myeloid leukemia (CML) and to analyze its clinical significance.
METHODS: The unmethylation level of miR-378 gene promoter in bone marrow mononuclear cells of 25 healthy donors and 53 patients with CML was detected by using real-time quantitative methylation-specific PCR (RQ-MSP).
RESULTS: The hypomethylation of miR-378 gene promoter was found in 17/53 (32.1%) patients, but only in 1/25 (4.0%) of controls. The difference between the two groups was very statistically significant (P < 0.01). The frequency of miR-378 unmethylation in CML patients at chronic phase (CP), accelerated phase (AP) and blastic phase (BP) was 35.0% (14/40), 40.0% (2/5), and 12.5% (1/8), respectively. However, there were no significant differences in the unmethylation level of miR-378 among CML patients at different sexes, stages and karyotypes. No significant differences could be observed in age, white blood cell counts, platelet count, hemoglobin level and BCR/ABL1 transcript level (P > 0.05). CONCLUDSION: The miR-378 hypomethylation is a common molecular event in CML, especially at chronic or accelerated phases.

Liu LJ, Cao XJ, Zhou C, et al.
Construction of polycythemia vera protein interaction network and prediction of related biological functions.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
Here, polycythemia vera (PV)-related genes were screened by the Online Mendelian Inheritance in Man (OMIM), and literature pertaining to the identified genes was extracted and a protein-protein interaction network was constructed using various Cytoscape plugins. Various molecular complexes were detected using the Clustervize plugin and a gene ontology-enrichment analysis of the biological pathways, molecular functions, and cellular components of the selected molecular complexes were identified using the BiNGo plugin. Fifty-four PV-related genes were identified in OMIM. The protein-protein interaction network contains 5 molecular complexes with correlation integral values >4. These complexes regulated various biological processes (peptide tyrosinase acidification, cell metabolism, and macromolecular biosynthesis), molecular functions (kinase activity, receptor binding, and cytokine activity), and the cellular components were mainly concentrated in the nucleus, intracellular membrane-bounded organelles, and extracellular region. These complexes were associated with the JAK-STAT signal transduction pathway, neurotrophic factor signaling pathway, and Wnt signaling pathway, which were correlated with chronic myeloid leukemia and acute myeloid leukemia.

Kokate P, Dalvi R, Mandava S
A complex three-way translocation with deletion of the TP53 gene in a blast crisis chronic myeloid leukemia patient.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):1037 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome created by the reciprocal translocation t(9;22) (q34;q11), resulting in the chimeric BCR-ABL oncogene. Variant Ph' chromosome translocations involving additional chromosomes are seen in 5-10% of CML cases. In the present study, a novel case of Ph' chromosome-positive CML is reported, with a three-way translocation involving chromosomal regions, 9q34, 22q11.2 and 17p11.2, with additional secondary changes. The three-way translocation has resulted in a deletion of the TP53 gene located on the chromosome 17p13.1 locus. Deletion of the TP53 gene may be a major contributing factor in the development of resistance to imatinib and blast crisis.

Alikian M, Ellery P, Forbes M, et al.
Next-Generation Sequencing-Assisted DNA-Based Digital PCR for a Personalized Approach to the Detection and Quantification of Residual Disease in Chronic Myeloid Leukemia Patients.
J Mol Diagn. 2016; 18(2):176-89 [PubMed] Related Publications
Recent studies indicate that 40% of chronic myeloid leukemia patients who achieve sustained undetectable BCR-ABL1 transcripts on tyrosine kinase inhibitor therapy remain disease-free after drug discontinuation. In contrast, 60% experience return of detectable disease and have to restart treatment, thus highlighting the need for an improved method of identifying patients with the lowest likelihood of relapse. Here we describe the validation of a personalized DNA-based digital PCR (dPCR) approach for quantifying very low levels of residual disease, which involves the rapid identification of t(9;22) fusion junctions using targeted next-generation sequencing coupled with the use of a dPCR platform. t(9;22) genomic breakpoints were successfully mapped in samples from 32 of 32 patients with early stage disease. Disease quantification by DNA-based dPCR was performed using the Fluidigm BioMark platform on 46 follow-up samples from 6 of the 32 patients, including 36 samples that were in deep molecular remission. dPCR detected persistent disease in 81% of molecular-remission samples, outperforming both RT-dPCR (25%) and DNA-based quantitative PCR (19%). We conclude that dPCR for BCR-ABL1 DNA is the most sensitive available method of residual-disease detection in chronic myeloid leukemia and may prove useful in the management of tyrosine kinase inhibitor withdrawal.

Li C, Yichao J, Jiaxin L, et al.
Methylenetetrahydrofolate reductase gene polymorphism and risk of chronic myelogenous leukemia: a meta-analysis.
J BUON. 2015 Nov-Dec; 20(6):1534-45 [PubMed] Related Publications
PURPOSE: Reported evidence supports a role for methylenetetrahydrofolate reductase (MTHFR) in the risk of chronic myelogenous leykemia (CML). However, these reports arrived at non-conclusive and even conflicting results regarding the association between two common MTHFR polymorphisms (C677T and A1298C) and CML risk. Thus, a meta-analysis was carried out to clarify a more precise association between these two polymorphisms and the CML risk by updating the available publications.
METHODS: Pooled odds ratios (OR) with corresponding 95% confidence interval (95% CI) and stratification analysis were performed to estimate the relationship between MTHFR polymorphisms and the risk of CML under different genetic comparison models.
RESULTS: Data from the meta-analysis showed no significant association between MTHFR C677T polymorphism and CML risk. However, significant associations were found between MTHFR A1298C variants and CML risk under homozygous comparison model (CC vs AA, OR=1.62, 95% CI=1.11-2.36, p=0.01) and dominant comparison model (CC+AC vs AA, OR=1.68, 95% CI=1.17-2.43, p=0.005) in overall population; especially more obvious impacts were noticed for Asian populations in subgroup analysis for homozygous model (CC vs AA, OR=2.00, 95% CI=1.25-3.21, p=0.004) and dominant model (CC+AC vs AA, OR=2.49, 95% CI=1.42-4.36, p=0.001), but this did not apply in Caucasian populations.
CONCLUSION: The results of this meta-analysis suggested no significant association between MTHFR C677T polymorphism and CML risk, while an increased CML risk was noticed for 1298C variant carriers, especially in Asian populations but not in Caucasian populations, which suggested ethnicity differences between MTHFR A1298C polymorphisms and risk of CML.

Liu B, Zhang W, Ma H
Complete cytogenetic response to Nilotinib in a chronic myeloid leukemia case with a rare e13a3(b2a3) BCR-ABL fusion transcript: A case report.
Mol Med Rep. 2016; 13(3):2635-8 [PubMed] Related Publications
In the present study, an atypical case of chronic myeloid leukemia (CML) in a 32-year-old male was reported. CML cases with e13a3 breakpoint cluster region (BCR)-ABL transcripts are extremely rare. Reverse transcription quantitative‑polymerase chain reaction (RT-qPCR) was initially negative due to the primer corresponding to ABL a2 sequences and diagnosis was based upon analysis of the bone marrow smear, fluorescence in situ hybridization and karyotype analysis. RT‑qPCR analysis with the ABL primer, which was located in ABL exon 3 to enable the detection of fusions with either ABL a2 or exon a3 demonstrated the presence of the BCR‑ABL fusion transcript e13a3. The patient responded well to Nilotinib and achieved a complete cytogenetic response after 3 months.

Du Q, Li Q, Chen X, et al.
[Calibration of false positive result in detection of BCR/ABL using fluorescence in situ hybridization].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016; 33(1):22-5 [PubMed] Related Publications
OBJECTIVE: To explore the effect of false positive signals during detection of BCR/ABL fusion gene by fluorescence in situ hybridization (FISH), and develop a method for calibration.
METHODS: Normal specimens were mixed with BCR/ABL positive specimens in which presented signal pattern of 1-red-2-green-1-fusion (1R2G1F) using dual color dual fusion (DCDF) probes and 1-red-1-green-1-fusion (1R1G1F) using extra signal (ES) probes in different proportions. Mixed samples were detected using DCDF and ES probes. Results of DCDF probes, ES probe before calibration, ES probes after calibration and theoretical results were compared by binomial distribution in different proportions.
RESULTS: The rate of false positive signals has risen with increase of negative rate. A significant difference was found between theoretical proportion and results without calibration in negative level, 5%, 10% and 25% positive level (P<0.05). There was no significant difference between theoretical proportion and results without calibration in 50% and 90% positive level (P>0.05). Also there was no significant difference between theoretical proportion and calibrated results (P>0.05).
CONCLUSION: Calibration of FISH result can delimitate the effect of false positives, and can provide more reliable results in cases with low level positive rates.

Lavrov AV, Chelysheva EY, Smirnikhina SA, et al.
Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.
BMC Genet. 2016; 17 Suppl 1:14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary resistance to standard therapy. Whole exome sequencing is a good tool for unbiased search of genetic variations important for prognosis of survival and therapy efficacy in many cancers. We apply this approach to CML patients with optimal response and failure of tyrosine kinase therapy.
RESULTS: We analyzed exome variations between optimal responders and failures and found 7 variants in cancer-related genes with different genotypes in two groups of patients. Five of them were found in optimal responders: rs11579366, rs1990236, rs176037, rs10653661, rs3803264 and two in failures: rs3099950, rs9471966. These variants were found in genes associated with cancers (ANKRD35, DNAH9, MAGEC1, TOX3) or participating in cancer-related signaling pathways (THSD1, MORN2, PTCRA).
CONCLUSION: We found gene variants which may become early predictors of the therapy outcome and allow development of new early prognostic tests for estimation of therapy efficacy in CML patients. Normal genetic variation may influence therapy efficacy during targeted treatment of cancers.

Naren D, Wu J, Gong Y, et al.
Niemann-Pick disease type C1(NPC1) is involved in resistance against imatinib in the imatinib-resistant Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI.
Leuk Res. 2016; 42:59-67 [PubMed] Related Publications
Niemann-Pick disease type C1 (NPC1) is involved in cholesterol trafficking and may normally function as a transmembrane efflux pump. Previous studies showed that its dysfunction can lead to cholesterol and daunorubicin accumulation in the cytoplasmic endosomal/lysosomal system, lead to Niemann-Pick disease and resistance to anticancer drugs. In the present study, NPC1 was shown by microarray analysis to be more highly expressed in the Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI, an imatinib-resistant variant of SUP-B15/S cells without bcr-abl gene mutation established in our lab. Further investigation revealed a defect in the functional capacity of the NPC1 protein demonstrated by filipin staining accompanied by a lower intracellular imatinib mesylate(IM) concentration by high-performance liquid chromatography in SUP-B15/RI compared with SUP-B15/S cells. Furthermore, U18666A, an inhibitor of NPC1 function, was used to block cholesterol trafficking to imitate the NPC1 defect in SUP-B15/S cells, leading to higher NPC1 expression, stronger filipin fluorescence, lower intracellular IM concentrations and greater resistance against IM. Samples from non-mutated relapsed Ph+ ALL patients also showed higher NPC1 expression compared with IM-sensitive patients. Our experiment may reveal a new mechanism of IM resistance in Ph+ ALL.

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
BCR-ABL Translocation in Chronic Myeloid LeukaemiaTranslocationABL1 (9q34.1)BCR (22q11.23)

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.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. Chronic Myeloid Leukemia, Cancer Genetics Web: Accessed:

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