Khajapeer Kalubai Vari, Baskaran Rajasekaran
Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry 605014, India.
Leuk Res Treatment. 2015;2015:757694. doi: 10.1155/2015/757694. Epub 2015 Dec 3.
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.
慢性髓性白血病（CML）是一种血液系统恶性肿瘤，它是由于9号染色体上c-阿贝尔森（ABL）原癌基因的3'序列与22号染色体上截短的断裂点簇区域（BCR）的5'序列发生相互易位而产生的。BCR-ABL是一种功能性癌蛋白p210，它表现出组成型激活的酪氨酸激酶，导致造血干细胞的基因组改变。BCR-ABL特异性酪氨酸激酶抑制剂（TKIs）成功地阻断了CML的进展。然而，由于BCR-ABL突变和过表达导致的耐药性仍然是一个问题。热休克蛋白（Hsps）作为分子伴侣，促进新生多肽的正确折叠。它们在应激条件下的表达增加，通过稳定未折叠或错误折叠的肽来保护细胞。Hsp90是主要的哺乳动物蛋白，BCR-ABL需要它来稳定和成熟。Hsp90抑制剂会破坏BCR-ABL蛋白的结合，从而导致异蛋白复合物的形成，最终被泛素-蛋白酶体途径降解。许多已进入各种临床试验的新型Hsp90抑制剂的结果令人鼓舞。本综述旨在通过利用Hsp90特异性抑制剂来探讨CML治疗的当前进展。
