View the Current Issue

Article

  • The EMBO Journal (2005) 24, 368 - 381
  • doi:10.1038/sj.emboj.7600521

Published online: 6 January 2005

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

Jing Wang1, Hiromi Iwasaki2, Andrei Krivtsov3, Phillip G Febbo4, Aaron R Thorner4, Patricia Ernst1, Ema Anastasiadou5,a, Jeffery L Kutok2, Scott C Kogan6, Sandra S Zinkel1, Jill K Fisher1, Jay L Hess7, Todd R Golub4, Scott A Armstrong3, Koichi Akashi2 and Stanley J Korsmeyer1

  1. Department of Pathology and Medicine, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  2. Department of Pathology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
  3. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  5. Harvard Institutes of Medicine, Harvard Medical School, Boston, MA, USA
  6. Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco, CA, USA
  7. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Correspondence to:

Stanley J Korsmeyer, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel.: +1 617 632 6402; Fax: +1 617 632 6401; E-mail: stanley_korsmeyer@dfci.harvard.edu

aCurrent address: Genetics Laboratory, Foundation of Bioacademical Research, Academy of Athens, Greece

Received 23 September 2004; Accepted 24 November 2004

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.

  • Keywords:

    • granulocyte/macrophage progenitors,
    • leukemogenesis,
    • MLL-CBP,
    • myeloproliferative disease