Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

Abstract

BCR-ABL kinase domain (K D ) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-K D mutations in chronic phase (n D 41), late chronic phase (n D 33) and accelerated phase (n D 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-K D . Occurrence of mutations was found associated with elevated platelet count (p D 0.037) and patients of male sex (p D 0.049). The median overall survival and event free survival of CML patients (n D 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-K D mutation screening in late chronic phase CML patients for improved clinical management of disease.

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations

“…In this cohort, the percentage of males increased from 59.1% to 81.8% when comparing groups A and B. This gender distribution was also observed in other studies, which indicated that regular detection of ACAs and/or KD mutations was more important in male patients …”

“…This gender distribution was also observed in other studies, which indicated that regular detection of ACAs and/or KD mutations was more important in male patients. 5,7 In conclusion, we confirmed the role of ACAs and/or KD mutations in CML progression and demonstrated that both of these abnormalities…”

“…Current studies have found that the incidence of additional chromosomal abnormalities (ACAs) is approximately 5% in the chronic phase (CP) of CML patients, 30% in the accelerated phase (AP) and 80% in the blast phase (BP) . Hence, ACAs are considered an intrinsic factor in the progression of CML patients with a negative impact on survival and prognosis . ACAs were subdivided into major and minor routes, as initially proposed by Mitelman, based only on the frequencies of the ACAs .…”

Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan

“…DNA was isolated from collected blood samples by using GeneJET Genomic DNA Purification Kit (ThermoFisher Scientific CAT# K0721) following manufacturer's instructions. This was followed by the integrity check of isolated DNA through Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene amplification 17 , 18 .…”

Identifying Dysregulated lncRNA-Associated ceRNA Network Biomarkers in CML Based on Dynamical Network Biomarkers

“…Chronic myeloid leukemia (CML) is a clonal malignant proliferative disease of hematopoietic stem cells (HSCs). e main hallmark is the formation of BCR-ABL fusion gene at the molecular level [1]. BCR-ABL is a chimeric oncogene arising from t (9; 22) (q34; q11) chromosomal translocation.…”