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Modeling de novo leukemogenesis from human cord blood with MN1 and NUP98HOXD13

Suzan Imren, Michael Heuser, Maura Gasparetto, Philip A. Beer, Gudmundur L. Norddahl, Ping Xiang, Ling Chen, Tobias Berg, Garrett W. Rhyasen, Patricia Rosten, Gyeongsin Park, Yeonsook Moon, Andrew P. Weng, Connie J. Eaves and R. Keith Humphries

Key points

  • MN1 promotes self-renewal and inhibits differentiation of CD34+ cord blood cells in vitro.

  • De novo leukemogenesis is engineered by MN1 and NUP98HOXD13 expression in cord blood cells.

Abstract

Leukemic transformation of human cells is a complex process. Here we show that forced expression of MN1 in primitive human cord blood (CB) cells maintained on stromal cells in vitro induces a transient, but not serially transplantable, myeloproliferation in engrafted mice. However, co-transduction of an activated HOX gene (NUP98HOXD13) with MN1 induces a serially transplantable acute myeloid leukemia (AML). Further characterization of the leukemic cells generated from the dually transduced cells revealed activation of stem cell gene expression signatures also found in primary human AML. These findings reveal a new forward genetic model of human leukemogenesis and further highlight the relevance of homeobox transcription factors in the transformation process.

  • Submitted April 3, 2014.
  • Accepted October 15, 2014.