Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 ( Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL . Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL –transduced lin − CD34 + human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL –inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2–STAT5. Moreover, we identified an AHI-1–BCR-ABL–JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2–STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML. Footnotes Abbreviations used: Ahi-1, Abelson helper integration site 1; BFU-E, burst-forming-units-erythroid; CB, cord blood; CFC, colony-forming cell; CFU-GEMM, colony-forming units-granulocyte-erythrocyte-monocyte-megakaryocyte; CFU-GM, colony-forming units-granulocyte-macrophage; CML, chronic myeloid leukemia; co-IP, coimmunoprecipitation; Dox, doxycycline; DS, dasatinib; GF, growth factor; IM, imatinib mesylate; IRES, internal ribosomal entry site; LTC-IC, long-term culture-initiating cell; NL, nilotinib; Q-RT-PCR, quantitative real-time-PCR; PI3K, phosphatidylinositol 3-kinase; SFM, serum-free medium; TKI, tyrosine kinase inhibitor. © 2008 Zhou et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ). Submitted: 29 October 2007 Accepted: 19 September 2008
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AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells
Zhou, Liang L.; Zhao, Yun; Ringrose, Ashley; DeGeer, Donna; Kennah, Erin; Lin, Ann E.-J.; Sheng, Guoqing; Li, Xiao-Jiang; Turhan, Ali; Jiang, Xiaoyan
Follow The Journal of Experimental Medicine
, Volume 205 (11): 2657
Rockefeller University Press – Oct 27, 2008
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