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Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance.

Rejali L, Poopak B, Hasanzad M, Sheikhsofla F, Varnoosfaderani AS, Safari N, Rabieipoor S - Iran J Cancer Prev (2015)

Bottom Line: A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib.Finally the results were approved by direct sequencing.The G250E, V379I and L384M mutations were found in three different cases with failure molecular response.

View Article: PubMed Central - PubMed

Affiliation: MSc in Molecular Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, IR Iran.

ABSTRACT

Background: Chronic myelogenous leukemia (CML) is a kind of hematopoietic stem-cell cancer. A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.

Objectives: One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.

Patients and methods: The study was performed on 39 CML patients with Imatinib resistance. Basic hematologic parameters in blood samples were checked to identify hematologic response. To identify molecular response, BCR-ABL/ABL ratio was assessed by Real-time PCR. The ABL kinase domain amplification was performed by PCR. Restriction fragment length polymorphism (RFLP) was performed to detect four common mutations (T315I, Y253H, E255K and M351T). Finally the results were approved by direct sequencing.

Results: In this study, the Y253H mutation, detected by RFLP method and confirmed by direct sequencing, was the prevalent ABL kinase domain mutation in these 39 CML patients. The G250E, V379I and L384M mutations were found in three different cases with failure molecular response. CML patients with these four ABL kinase domain mutations cannot achieve major molecular response (MMR). In addition, complete hematologic response (CHR) was observed only in the V379I mutated case and not in other mutated patients.

Conclusions: Identification of ABL kinase domain mutations may be used as a proper and useful method for improving therapeutic strategies, avoiding delay in treatment and excessive expenditure in CML patients with Imatinib resistance.

No MeSH data available.


Related in: MedlinePlus

Breakpoints in the ABL and BCR Genes and the Encoded Protein in the BCR-ABL FusionThe transcripts of the BCR-ABL fusion gene usually contain one of the two BCR-ABL junctions: e13a2 (b2a2) and e14a2 (b3a2) (4).
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A2334FIG1: Breakpoints in the ABL and BCR Genes and the Encoded Protein in the BCR-ABL FusionThe transcripts of the BCR-ABL fusion gene usually contain one of the two BCR-ABL junctions: e13a2 (b2a2) and e14a2 (b3a2) (4).

Mentions: Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy accounted for 15% to 20% of diagnosed adult CML patients (1). The hallmark of CML in 95% of patients is a chromosomal reciprocal translocation which forms a kind of BCR-ABL fusion gene and an abnormal short chromosome 22, defined as the Philadelphia chromosome (1, 2). This abnormal chromosome can be detected in mitotic cells under microscope using traditional cytogenetic techniques to prepare karyotype for the cases or using the fluorescent in situ hybridization (FISH) technique in which probes hybridize to the fusion gene and radiate fluorescent signals. BCR gene and ABL proto-oncogene are located on chromosomes 22 and 9, respectively. The break point junctions in BCR-ABL mostly occur in exon b2 or b3 of BCR gene and exon a2 of ABL gene to create b2a2 or b3a2 fusion (Figure 1). Transcripts of the fusion gene are mostly p190 and p210. The presence of constitutively activated tyrosine kinase BCR-ABL has a main role in the pathogenesis of disease (2). The discussed leukemia starts with indolent chronic phase (CP) with variable durations that would progress to the second stage of disease, accelerated phase (AP), if left untreated and within a short time blastic phase (BP) is occurred (3).


Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance.

Rejali L, Poopak B, Hasanzad M, Sheikhsofla F, Varnoosfaderani AS, Safari N, Rabieipoor S - Iran J Cancer Prev (2015)

Breakpoints in the ABL and BCR Genes and the Encoded Protein in the BCR-ABL FusionThe transcripts of the BCR-ABL fusion gene usually contain one of the two BCR-ABL junctions: e13a2 (b2a2) and e14a2 (b3a2) (4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581365&req=5

A2334FIG1: Breakpoints in the ABL and BCR Genes and the Encoded Protein in the BCR-ABL FusionThe transcripts of the BCR-ABL fusion gene usually contain one of the two BCR-ABL junctions: e13a2 (b2a2) and e14a2 (b3a2) (4).
Mentions: Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy accounted for 15% to 20% of diagnosed adult CML patients (1). The hallmark of CML in 95% of patients is a chromosomal reciprocal translocation which forms a kind of BCR-ABL fusion gene and an abnormal short chromosome 22, defined as the Philadelphia chromosome (1, 2). This abnormal chromosome can be detected in mitotic cells under microscope using traditional cytogenetic techniques to prepare karyotype for the cases or using the fluorescent in situ hybridization (FISH) technique in which probes hybridize to the fusion gene and radiate fluorescent signals. BCR gene and ABL proto-oncogene are located on chromosomes 22 and 9, respectively. The break point junctions in BCR-ABL mostly occur in exon b2 or b3 of BCR gene and exon a2 of ABL gene to create b2a2 or b3a2 fusion (Figure 1). Transcripts of the fusion gene are mostly p190 and p210. The presence of constitutively activated tyrosine kinase BCR-ABL has a main role in the pathogenesis of disease (2). The discussed leukemia starts with indolent chronic phase (CP) with variable durations that would progress to the second stage of disease, accelerated phase (AP), if left untreated and within a short time blastic phase (BP) is occurred (3).

Bottom Line: A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib.Finally the results were approved by direct sequencing.The G250E, V379I and L384M mutations were found in three different cases with failure molecular response.

View Article: PubMed Central - PubMed

Affiliation: MSc in Molecular Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, IR Iran.

ABSTRACT

Background: Chronic myelogenous leukemia (CML) is a kind of hematopoietic stem-cell cancer. A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.

Objectives: One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.

Patients and methods: The study was performed on 39 CML patients with Imatinib resistance. Basic hematologic parameters in blood samples were checked to identify hematologic response. To identify molecular response, BCR-ABL/ABL ratio was assessed by Real-time PCR. The ABL kinase domain amplification was performed by PCR. Restriction fragment length polymorphism (RFLP) was performed to detect four common mutations (T315I, Y253H, E255K and M351T). Finally the results were approved by direct sequencing.

Results: In this study, the Y253H mutation, detected by RFLP method and confirmed by direct sequencing, was the prevalent ABL kinase domain mutation in these 39 CML patients. The G250E, V379I and L384M mutations were found in three different cases with failure molecular response. CML patients with these four ABL kinase domain mutations cannot achieve major molecular response (MMR). In addition, complete hematologic response (CHR) was observed only in the V379I mutated case and not in other mutated patients.

Conclusions: Identification of ABL kinase domain mutations may be used as a proper and useful method for improving therapeutic strategies, avoiding delay in treatment and excessive expenditure in CML patients with Imatinib resistance.

No MeSH data available.


Related in: MedlinePlus