PMID:18936234

Citation	Zhou, LL, Zhao, Y, Ringrose, A, DeGeer, D, Kennah, E, Lin, AE, Sheng, G, Li, XJ, Turhan, A and Jiang, X (2008) AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J. Exp. Med. 205:2657-71
Abstract	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.
Links	PubMed PMC2571939 Online version:10.1084/jem.20072316
Keywords	Animals; Blotting, Western; Cell Line; Cell Transformation, Neoplastic/metabolism; DNA Primers/genetics; Flow Cytometry; Fusion Proteins, bcr-abl/metabolism; Gene Expression Regulation, Neoplastic/physiology; Hematopoietic Stem Cells/drug effects; Hematopoietic Stem Cells/metabolism; Humans; Immunoprecipitation; Janus Kinase 2/metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism; Mice; Phosphorylation; Piperazines; Protein-Tyrosine Kinases/antagonists & inhibitors; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Pyrimidines; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:AHI1	involved_in	GO:0045927: positive regulation of growth	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:AHI1		GO:0045927: positive regulation of growth	ECO:0000314:		P		Figure 1 B Table I.	complete CACAO 2803
HUMAN:AHI1		GO:0045597: positive regulation of cell differentiation	ECO:0000316:	UniProtKB:Q8NEY0	P		Fig 8 C: Show genetic interaction between Ahi1 and BCR-ABL. Figure: 8 E	complete

References

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