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The Nucleus

, Volume 62, Issue 2, pp 155–164 | Cite as

Genetics and tyrosine kinase inhibitors of chronic myeloid leukemia

  • Bani Bandana GangulyEmail author
  • Nitin N. Kadam
Review Article
First Online:
  • 35 Downloads

Abstract

Chronic myeloid leukemia (CML) is caused by a reciprocal translocation between 9q34 and 22q11, which produces a chimeric BCR-ABL oncogene located on the Philadelphia chromosome i.e. rearranged 22. The fusion gene implicates in the overexpression of tyrosine kinase through binding with ATP in signal transduction. Therefore, targeted drug development aimed at inhibitors of tyrosine kinase (TKI) and formulated imatinib, which resulted in miraculous disease free survival in majority of the CML patients. However, drug-resistance remained a problem due mainly to emergence of missense point mutations in and around the BCR-ABL kinase domain. Loss of its sensitivity to leukemic stem cells guided development of altered TKIs such as dasatinib, nilotinib, bosutinib and ponatinib—each having specific sensitivity to different amino acid residues (T315I, Y253F/H, E255K/V, M351T, G250E, F359C/V, H396R/P, M244V, E355G, F317L, M237I, Q252H/R, D276G, L248V, F486S), have been implicated in ~ 85% of CML. At chromosomal level, trisomy 8, isochromosome 17q, amplification of the Philadelphia chromosome, additional translocations and complex karyotype are described in TKI-resistant CML. Therefore, mutational events at kinase domain and additional chromosome abnormalities could be considered for development and initiation of TKI-therapy, and cross-talk of complex mutations could lead to formulation of personalized TKI.

Keywords

Chronic myeloid leukemia BCR-ABL domain mutations Complex karyotype Tyrosine kinase inhibitors 
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Notes

Acknowledgement

The authors wish to acknowledge the Mahatma Gandhi Mission Trust for supporting this publication.

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© Archana Sharma Foundation of Calcutta 2019

Authors and Affiliations

  1. 1.MGM Center for Genetic Research and DiagnosisMGM New Bombay HospitalNavi MumbaiIndia
  2. 2.MGM Institute of Health SciencesNavi MumbaiIndia

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