A novel in-frame 231bp deletion mutation in ABL1 kinase activation loop

Abstract

Tyrosine kinase domain (TKD) mutation is one of the most common causes for tyrosine kinase inhibitors' resistance in patients with chronic myeloid leukemia (CML). Mutations in the exon 7 of ABL1 gene are one of the most common TKD mutations, especially in the Indian population, but they are frequently underreported, and their clinical significance is not clear. We are reporting a novel ABL1 exon 7 mutation in a previously diagnosed and treated patient CML who presented at the blast crisis stage. Cytogenetic studies showed multiple copies of Philadelphia (Ph) chromosome along with isochromosome 17. Kinase domain mutation studies showed a novel 231bp in-frame deletion mutation (p. 372_448del) in the activation loop of BCR-ABL1 chimeric protein. The given mutation would result in a complete loss of activation loop, including DFG domain-regulating activation status of the catalytic domain. This mutation, along with cytogenetic abnormalities, could have contributed to progression to blast crisis.

Keywords

ABL1 exon 7 mutation - chronic myeloid leukemia - novel mutation - tyrosine kinase inhibitor resistance

Publikationsverlauf

Artikel online veröffentlicht:
08. Juni 2021

• References

• 1 Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L. et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23: 1054-61
• 2 Quintás-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control 2009; 16: 122-31
• 3 Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A. et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003; 102: 276-83
• 4 Alikian M, Gerrard G, Subramanian PG, Mudge K, Foskett P, Khorashad JS. et al. BCR-ABL1 kinase domain mutations: Methodology and clinical evaluation. Am J Hematol 2012; 87: 298-304
• 5 Curvo RP, Zalcberg IR, Scholl V, Pires V, Moellmann-Coelho A, Moreira MA. et al. A recurrent splicing variant without c-ABL exon 7 in imatinib-resistant patients. Leuk Res 2008; 32: 508-10
• 6 Patkar N, Ghodke K, Joshi S, Mascerhenas R, Dusseja S. et al. Characteristics of BCR-ABL kinase domain mutations in chronic myeloid leukemia from India: Not just missense mutations but insertions and deletions are also associated with TKI resistance. Leuk Lymphoma 2016; 57: 2653-60
• 7 Reddy EP, Aggarwal AK. The ins and outs of bcr-abl inhibition. Genes Cancer 2012; 3: 447-54
• 8 Lamontanara AJ, Gencer EB, Kuzyk O, Hantschel O. Mechanisms of resistance to BCR-ABL and other kinase inhibitors. Biochim Biophys Acta 2013; 1834: 1449-59
• 9 Jones D, Kamel-Reid S, Bahler D, Dong H, Elenitoba-Johnson K, Press R. et al. Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia: A report of the association for molecular pathology. J Mol Diagn 2009; 11: 4-11
• 10 Lee TS, Ma W, Zhang X, Giles F, Cortes J, Kantarjian H. et al. BCR-ABL alternative splicing as a common mechanism for imatinib resistance: Evidence from molecular dynamics simulations. Mol Cancer Ther 2008; 7: 3834-41