Identification Of Mutations In Bcr-Abl Gene In Newly Diagnosed Indian Patients With Chronic Myelogenous Leukemia (CML)

Mutations in Bcr-Abl gene is responsible for resistance after Imatinib treatment in 30-60% of the cases. Currently the data does not support testing for these mutations in Imatinib naïve cases. However there is a data emerging that suggest that base line mutations in the Bcr-Abl gene do exist even before Imatinib is started, especially in patients with high SOKAL score. In India the failure rate of Imatinib is higher in comparison to western literature because patients are detected for CML chronic phase (CP) at a later stage. This study was designed to identify mutations in Abl-KD in Indian CML patients with no previous exposure to tyrosine kinase inhibitor.

This study targeted a cohort of CML-CP patients (n=47) without prior TKI exposure. KD mutations were analyzed by direct sequencing.

A total of 47 samples were evaluated, out of which 2 samples were identified to have the same variation. This heterozygous missense variation (A206D) in the Abl1 gene was located on SH2 domain of Exon 4. The change was from C>A in codon 206, which caused a protein change from Alanine to Aspartic acid (p.A206D). By using the mutation taster software, this change was predicted to be disease causing with a high probability of .99 (∞1). One of the patients died within one year of diagnosis in spite of imatinib treatment.

A novel mutation with putative pathogenicity was identified in the TKI-naïve Indian CML patients, supporting the concept that naturally occurring KD mutations are present in leukemic cell prior to drug exposure.

No relevant conflicts of interest to declare.