Abstract
Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors.
Highlights
Leukemia is a type of blood cancer in which unusual raise in number of white blood cells is found
The mark of chronic myeloid leukemia (CML) is the presence of shortened Philadelphia chromosome (Ph) that occurs due to reciprocal translocation between chromosome 9 and chromosome 22 [(9;22) (q34;q11)], thereby eventually culminating in the genesis of the break point cluster region (BCR)-ABL oncogene
Bosutinib is recommended for imatinib resistance CML patients as well as in recently diagnosed CML patients in chronic phase [41]
Summary
Leukemia is a type of blood cancer in which unusual raise in number of white blood cells is found. Four types of leukemia are recognized by most cancer registries [1]. They are acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL). CML is a hematoproliferative neoplasm that is marked by uncontrolled myeloid cell divisions in bone marrow [2]. CML accounts for ∼20% of all leukemia cases in adults in western population [5]. The mark of CML is the presence of shortened Philadelphia chromosome (Ph) that occurs due to reciprocal translocation between chromosome 9 and chromosome 22 [(9;22) (q34;q11)], thereby eventually culminating in the genesis of the BCR-ABL oncogene. Fusion at different break points in BCR gene locus produces 3 different oncoproteins, namely, p190, p210, and p230. p190 causes ALL [7]; p210 is the major protein involved in CML [2]. p230 is correlated with a mild form of CML
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