Association Of BCR-ABL Alternative Splice Variants with Disease Progression, Treatment Response and Survival in Chronic Myeloid Leukemia Patients Treated with Firstline imatinib Monotherapy

Nawaf Alanazi, Zafar Iqbal, Tanveer Akhtar, Ahmad M. Khalid, Aamer Aleem, Saba Shahzadi, Afia M. Akram, Mahmood Rasool, Ijaz H. Shah, Muhammad Khalid, Mudassar Iqbal, Abid Jameel, Zeba Aziz, Muhammad Farooq Sabar, Maryam AlMajed, Buthinah AlShehab, Sarah AlMukhaylid, Nouf AlMutairi, Dhay Salah Almaghlouth, Alhanoof Rashid A Alsuwaidani, Muhammad Arshad, Rashid Ayub, Khaled Aljarrah, Amer Mahmood


Background: Alternative RNA splicing has diverse biological effects in heath as well as disease. It also contributes to cancer onset and progression. Chronic Myeloid Leukemia (CML) results due to BCR-ABL fusion oncogene that is created due to chromosomal translocation t [9; 22] [q34; q11]). BCR-ABL is target of tyrosine kinase inhibitors (TKIs). BCR-ABL through alternative splicing can generate b2a2, b3a2 and some other rare splicing variants. BCR-ABL variants may vary in their response to TKI treatment and disease progression potential, which is a major factor contributing to dismal treatment outcome in CML. Objective: The objective of this study is to investigate correlation of BCR-ABL splice variants with TKI treatment outcome and survival in three phases of CML that has rarely been studied previously.

Methods: BCR-ABL splice variants were studied using reverse transcriptase PCR (RT-PCR). in 70 CML patients from three phases of CML who were receiving imatinib (TKI) treatment.

Results: Frequencies of different BCR/ABL splice variants like b3a2, b2a2 and b3a2+b2a2 were 49 (70%), 15 (21.4%) and 6 (8.6%), respectively. Splice variant b2a2 were more common (53.3%) in chronic phase CML (CP-CML) while b3a2 had higher frequency in advanced phases of CML (44.9%). CML patients with b2a2 transcript had better complete cytogenetic response and major molecular response to TKI treatment overall (100% vs. 24.5%) as well as in CP-CML (100% vs. 85.7%) and superior survival when compared to patients with b3a2 splice variant. All patients who died had male gender, less than 33 years age, b3a2 transcript, advanced phases of CML and imatinib resistance.

Conclusions: Splice variant b3a2 was associated with CML progression, poorer survival and inferior treatment outcome as compared to b2a2. Further investigations on BCR-ABL splice variants and their roles in CML pathogenesis can provide deeper insights into CML biology and new targets for BCR-ABL positive leukemia treatment.          

Keywords: CML; BCR-ABL splice variants; Progression; Survival; Treatment outcome   

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