ABL Kinase Domain Mutations in Patients with Chronic Myeloid Leukemia in Jordan

Awidi, Abdalla; Ababneh, Nidaa A.; Magablah, Ahmad; Bsoul, Nazzal; Mefleh, Razan; Marei, Lina; Abbasi, Salah

doi:10.1089/gtmb.2012.0147

Cited by 12 publications

(9 citation statements)

References 21 publications

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“…Reviewing literature showed dissimilar opinions when associating TKD mutations with inferior outcomes-Awidi et al suggested ABL domain mutations to be liable for resistance; however, Abdullaev et al reported 15 out of 32 cases with a p.R362fs*21 mutation to be sensitive to TKI therapy and associate additional deletions to confer resistance to therapy. 19,20 Despite no TKD mutation, minCgR and mCgR was seen in case 16 (5q11.2) and 19 (5q14). This suggested chromosome 5 involvement (as the third partner in variant translocation) to be possibly associated with a poor prognostic consequence.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation

Shetty

Talker

Jain

et al. 2021

Asia-Pac J Clncl Oncology

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Background and aim: Molecular mechanism of translocation and outcome in variant chronic myeloid leukaemia (vCML) has been a topic of debate. While several cytogenetic studies suggest a low response to Imatinib Mesylate, others demonstrate a similar disease course in both classical and vCML. Besides, many studies comprehensively also link tyrosine kinase domain (TKD) mutations with aggressive clinical outcome. Thus, we aim to study the molecular mechanism of translocation, identify the third partner chromosomes and comment on the disease course and clinical outcome. Method:We cytogenetically characterised 25 vCML cases to determine the third partner chromosome, mechanism of translocation and prognostic outcome. We also compared vCML cases with and without TKD mutation to most appropriately outline the clinical consequence and ascertain the potent cause of unresponsiveness to treatment.Results: Third partner chromosome in variant translocation was defined by conventional and molecular cytogenetics. Although in our study most cases showed inadequate clinical response attributable to TKD mutation rather than variant translocation, we observed an inferior outcome in cases involving chromosome 5 as the third partner. Conclusion:Thus, we conclude that characterising and reporting new cases of variant translocations, involving various different chromosomes as third partner (with different breakpoints) by cytogenetics, will lead to a better understanding of the disease. To the best of our knowledge, this kind of delineate study has not been applied to precisely comment on the prospects of cytogenetically characterised vCML. K E Y W O R D S tyrosine kinase domain mutation, variant chronic myeloid leukaemia 1 INTRODUCTION Chronic myeloid leukaemia (CML) is the malignant transformation and abnormal proliferation of myeloid progenitor cells. An untreated CML is a bi or tri-phasic disease. European Leukaemia Net (ELN) 2009 characterizes chronic phase CML (CML-CP) by splenomegaly, increased neutrophils and <10% blasts; accelerated phase (CML-AP) by 10-19% blasts and thrombocytopenia unrelated to therapy and blast crises (CML-BC) by increased blasts in blood or bone marrow, clusters of blasts and extramedullary blast involvement. 1 Most patients are diagnosed in CML-CP which usually has an insidious onset. CML accounts for 15% of all leukaemias in adults and shows a slight male

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Section: Discussionmentioning

confidence: 99%

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation

Shetty

Talker

Jain

et al. 2021

Asia-Pac J Clncl Oncology

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“…Here, we found that the T315I mutation was the most common missense mutation, as previously described. 5,7,[13][14][15] The threonine 315 position, known as the gate keeper position, is located at the peripheral site of adenosine triphosphate binding, and its hydroxyl group provides critical hydrogen bonds for dasatinib, nilotinib, and imatinib binding. 16 When threonine is substituted by isoleucine, the TKI binding kinase domain is impaired, and drug resistance eventually develops.…”

Section: Discussionmentioning

confidence: 99%

The landscape of BCR‐ABL mutations in patients with Philadelphia chromosome‐positive leukaemias in the era of second‐generation tyrosine kinase inhibitors

Chien

Liu

Chen

et al. 2020

Hematological Oncology

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BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AACàAAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid

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“…To date, there have been 11 reports of the M244V mutation to the BCR-ABL fusion in the PubMed database (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…No additional mutations were observed in this patient. Awidi et al (14) reported 185 cases of CML initially treated with imatinib, of which 21 cases had mutations to BCR-ABL. Of these 21 cases, two (10%) had the M244V mutation.…”

Section: Discussionmentioning

confidence: 99%

Nilotinib rapidly reverses breakpoint cluster region-Abelson oncogene fusion gene and M244V mutations in a patient with chronic myelogenous leukemia: A case report

Shen¹,

Zhang²,

Shen³

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Chronic myelogenous leukemia (CML) is a condition characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), which leads to a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is referred to as the Philadelphia chromosome. At a molecular level, this translocation results in the formation of the BCR-ABL fusion oncogene, which translates into a BCR-ABL oncoprotein. Imatinib, nilotinib and dasatinib are three tyrosine kinase inhibitors that have been approved by the US Food and Drug Administration for the treatment of patients diagnosed with CML in the chronic phase (CML-CP). The present study describes the case of a patient with imatinib-resistant CML who, following two months of treatment with nilotinib, no longer exhibited detectable BCR-ABL fusion genes or M244V mutations. This suggests that nilotinib may be effective for treating CML cases in which the BCR-ABL fusion protein has an M244V mutation. IntroductionChronic myelogenous leukemia (CML) is a cancer of the white blood cells characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), which leads to a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This chromosomal translocation is known as the Philadelphia chromosome. At a molecular level, the rearrangement results in the formation of the BCR-ABL fusion oncogene, which translates into a BCR-ABL oncoprotein (1).The US Food and Drug Administration has approved three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, as first-line treatments for patients diagnosed with CML in the chronic phase (CML-CP) (2-5). Imatinib mesylate, otherwise known as Gleevec ® (Novartis Pharmaceuticals Corp., East Hanover, NJ, USA), was the first of the TKIs to receive approval; however, 20-40% of patients receiving imatinib as a first-line therapy are likely to eventually require an alternative treatment, due to intolerance or resistance to imatinib (5). It is recommended that, upon failure of imatinib treatment, patients with CML should be assessed for BCR-ABL kinase domain mutations, as this can indicate which TKI should be selected for continued therapy. Dasatinib and nilotinib have been demonstrated to retain efficacy against several of the mutations known to confer resistance to imatinib (6). Notably, a number of distinct mutations leading to decreased sensitivity to dasatinib and nilotinib have been found in in vitro and in vivo studies (7,8). Dasatinib is favored when patients have Y253H, E255K/V or F359C/V mutations in BCR-ABL. By contrast, nilotinib is more effective when V299L or F317L mutations are present (2). Despite this evidence, it remains unclear how the M244V mutation to the BCR-ABL fusion protein should affect the choice of treatment. The present study describes the effect of nilotinib therapy in a patient with imatinib-resistant CML. Case reportThis study was conducted in accordanc...

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ABL Kinase Domain Mutations in Patients with Chronic Myeloid Leukemia in Jordan

Cited by 12 publications

References 21 publications

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation

The landscape of BCR‐ABL mutations in patients with Philadelphia chromosome‐positive leukaemias in the era of second‐generation tyrosine kinase inhibitors

Nilotinib rapidly reverses breakpoint cluster region-Abelson oncogene fusion gene and M244V mutations in a patient with chronic myelogenous leukemia: A case report

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