title: Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML.
abstract: 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.
authors: Moores Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA.
authors: Miao-Chia
authors: MC
authors: Lo
authors: Luke F
authors: LF
authors: Peterson
authors: Ming
authors: M
authors: Yan
authors: Xiuli
authors: X
authors: Cong
authors: Fulai
authors: F
authors: Jin
authors: Wei-Jong
authors: WJ
authors: Shia
authors: Shinobu
authors: S
authors: Matsuura
authors: Eun-Young
authors: EY
authors: Ahn
authors: Yukiko
authors: Y
authors: Komeno
authors: Minh
authors: M
authors: Ly
authors: Hans B
authors: HB
authors: Ommen
authors: I-Ming
authors: IM
authors: Chen
authors: Peter
authors: P
authors: Hokland
authors: Cheryl L
authors: CL
authors: Willman
authors: Bing
authors: B
authors: Ren
authors: Dong-Er
authors: DE
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism*; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D050791:STAT Transcription Factors; D053612:Janus Kinases; D017493:Leukocyte Common Antigens