NDLI: Combination of JAK2 and HSP90 inhibitors: an effective therapeutic option in drug-resistant chronic myelogenous leukemia

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Combination of JAK2 and HSP90 inhibitors: an effective therapeutic option in drug-resistant chronic myelogenous leukemia

Content Provider	Semantic Scholar
Author	Chakraborty, Sandip N. Leng, Xiaohong Perazzona, Bastianella Sun, Xiaoping Lin, Yu-Hsi Arlinghaus, Ralph B.
Copyright Year	2016
Abstract	Recent studies suggest that JAK2 serves as a novel therapeutic target in Bcr-Abl+ chronic myelogenous leukemia (CML). We have reported the existence of an HSP90- associated high molecular weight network complex (HMWNC) that is composed of HSP90 client proteins BCR-ABL, JAK2, and STAT3 in wild type Bcr-Abl+ leukemic cells. Here we showed that the HSP90-HMWNC is present in leukemia cells from CML patients in blast stage, and in Imatinib (IM)-resistant 32Dp210 (T315I) leukemia cells. We found that the HSP90-HMWNC could be disassembled by depleting JAK2 with either Jak2-specific shRNA or treatment with JAK2 inhibitors (TG101209 or Ruxolitinib) and HSP90 inhibitor (AUY922). Combinational treatment with JAK2 and HSP90 inhibitors diminished the activation of BCR-ABL, JAK2 and its downstream targets. As a result, the IM-resistant 32Dp210 T315I cells underwent apoptosis. When administered in mice bearing 32Dp210 T315I leukemia, combinational therapy using Ruxolitinib and AUY922 prolonged the survival significantly. Thus, a combination of JAK2 and HSP90 inhibitors could be a powerful strategy for the treatment of CML, especially in IM-resistant patients.
Starting Page	201
Ending Page	208
Page Count	8
File Format	PDF HTM / HTML
PubMed reference number	27551334
Alternate Webpage(s)	https://doi.org/10.18632/genesandcancer.111
DOI	10.18632/genesandcancer.111
Journal	Genes & cancer
Volume Number	7
Language	English
Access Restriction	Open
Subject Keyword	AUY922 Apoptosis B-Cell Receptor Complex Blast Phase FANG vaccine Fusion Proteins, bcr-abl HSP90 Heat-Shock Proteins Janus kinase 2 Leukemia, B-Cell Leukemia, Myelocytic, Acute Myeloid Leukemia Myeloid Leukemia, Chronic Patients Stat3 protein TG101209 Wild Type abl Oncogene imatinib ruxolitinib
Content Type	Text
Resource Type	Article

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