Journal
BLOOD
Volume 120, Issue 7, Pages 1473-1484Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-12-395335
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Funding
- National Institutes of Health [CA104509, CA096735]
- Leukemia & Lymphoma Society (Fellowship) [5122-07]
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Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/ Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a). Approximately 30% of the identified common targets of microarray and ChIP-chip assays overlap with the human t(8;21)-gene expression molecular signature. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. Re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development, and promotes apoptosis of t(8;21)-positive cells. This study demonstrates the benefit of combining gene expression and promoter occupancy profiling assays to identify molecular and potential therapeutic targets in human cancers and describes a previously unappreciated signaling pathway involving t(8; 21) fusion proteins, CD45, and JAK/STAT, which could be a potential novel target for treating t(8; 21) AML. (Blood. 2012;120(7):1473-1484)
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