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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

ABL Domain Sequence in an Imatinib Resistant CML Patient With Y253H MutationThe nucleotide change T > C at nucleotide 253 was detectable in 2.56% of referred Imatinib resistant CML patients. The position of the mutation is circled.
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A2334FIG3: ABL Domain Sequence in an Imatinib Resistant CML Patient With Y253H MutationThe nucleotide change T > C at nucleotide 253 was detectable in 2.56% of referred Imatinib resistant CML patients. The position of the mutation is circled.

Mentions: More than 80% of CML patients, referred to Payvand Clinical and Specialty Laboratory to follow-up, were in the first line TKI therapy. Among them, 39 of 135 (28.8%) who showed Imatinib resistance criteria, entered the study. Of 39 selected resistant patients, 25 (64.1%) were male and 14 (35.9%) female. The predominance of the disease was observed among males. Hematology tests for measuring main indexes like white blood cells (WBC), platelet and basophil were performed on taken peripheral blood samples to determine the hematologic response to the therapy. Real-time PCR was performed to estimate molecular response by specifying the BCR-ABL/ABL copy numbers on the synthesized c-DNA. Twenty-five (63.2%) patients were categorized as failure molecular response, four (10.2%) were in warning category and 10 (26.3%) in optimal response according to the 2013 ELN guideline (10). CHR was not seen in any of resistant patients classified in failure and warning groups of molecular response. The results of RFLP method performed on ABL amplified kinase domain for unveiling the proportion of mutated and unmutated alleles of four selected common mutations. According to the direct RFLP results, among 39 selected patients tested for the common named mutations, only one of them showed the Y253H mutation. Four (10.25%) of 39 resistant patients showed mutations in ABL kinase domain as sequenced the ABL domain. Among these, the Y253H mutation was shown in one patient by RFLP method and confirmed by direct sequencing (Figures 2 and 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)

ABL Domain Sequence in an Imatinib Resistant CML Patient With Y253H MutationThe nucleotide change T > C at nucleotide 253 was detectable in 2.56% of referred Imatinib resistant CML patients. The position of the mutation is circled.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

A2334FIG3: ABL Domain Sequence in an Imatinib Resistant CML Patient With Y253H MutationThe nucleotide change T > C at nucleotide 253 was detectable in 2.56% of referred Imatinib resistant CML patients. The position of the mutation is circled.
Mentions: More than 80% of CML patients, referred to Payvand Clinical and Specialty Laboratory to follow-up, were in the first line TKI therapy. Among them, 39 of 135 (28.8%) who showed Imatinib resistance criteria, entered the study. Of 39 selected resistant patients, 25 (64.1%) were male and 14 (35.9%) female. The predominance of the disease was observed among males. Hematology tests for measuring main indexes like white blood cells (WBC), platelet and basophil were performed on taken peripheral blood samples to determine the hematologic response to the therapy. Real-time PCR was performed to estimate molecular response by specifying the BCR-ABL/ABL copy numbers on the synthesized c-DNA. Twenty-five (63.2%) patients were categorized as failure molecular response, four (10.2%) were in warning category and 10 (26.3%) in optimal response according to the 2013 ELN guideline (10). CHR was not seen in any of resistant patients classified in failure and warning groups of molecular response. The results of RFLP method performed on ABL amplified kinase domain for unveiling the proportion of mutated and unmutated alleles of four selected common mutations. According to the direct RFLP results, among 39 selected patients tested for the common named mutations, only one of them showed the Y253H mutation. Four (10.25%) of 39 resistant patients showed mutations in ABL kinase domain as sequenced the ABL domain. Among these, the Y253H mutation was shown in one patient by RFLP method and confirmed by direct sequencing (Figures 2 and 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