Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML.

Academic Article

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

    Published In

  • Blood  Journal

    • Keywords

  • Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Transformation, Neoplastic, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, DNA, Neoplasm, Enzyme Activation, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Gene Regulatory Networks, Genes, Neoplasm, Humans, Janus Kinases, Leukemia, Myeloid, Acute, Leukocyte Common Antigens, Mice, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Reproducibility of Results, STAT Transcription Factors, Signal Transduction, Translocation, Genetic

    • Digital Object Identifier (doi)

    Author List

  • Lo M-C; Peterson LF; Yan M; Cong X; Jin F; Shia W-J; Matsuura S; Ahn E-Y; Komeno Y; Ly M

    • Start Page

  • 1473

    • End Page

  • 1484

    • Volume

  • 120

    • Issue

  • 7