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.
Original language | English (US) |
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Pages (from-to) | 201-208 |
Number of pages | 8 |
Journal | Genes and Cancer |
Volume | 7 |
Issue number | 5-6 |
DOIs | |
State | Published - May 2016 |
Keywords
- Bcr-Abl
- CML
- Drug-resistance
- HSP90
- JAK2
- Network complex
ASJC Scopus subject areas
- Genetics
- Cancer Research