Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.

Published

Journal Article

Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.

Full Text

Cited Authors

  • Wang, J; Iwasaki, H; Krivtsov, A; Febbo, PG; Thorner, AR; Ernst, P; Anastasiadou, E; Kutok, JL; Kogan, SC; Zinkel, SS; Fisher, JK; Hess, JL; Golub, TR; Armstrong, SA; Akashi, K; Korsmeyer, SJ

Published Date

  • January 26, 2005

Published In

Volume / Issue

  • 24 / 2

Start / End Page

  • 368 - 381

PubMed ID

  • 15635450

Pubmed Central ID

  • 15635450

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7600521

Language

  • eng

Conference Location

  • England