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

Abstract

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.

• Authors: Jing Wang, Hiromi Iwasaki, Andrei Krivtsov, Phillip G Febbo, Aaron R Thorner, Patricia Ernst, Ema Anastasiadou, Jeffery L Kutok, Scott C Kogan, Sandra S Zinkel, Jill K Fisher, Jay L Hess, Todd R Golub, Scott A Armstrong, Koichi Akashi, Stanley J Korsmeyer
• Journal: The EMBO journal (EMBO J) Vol. 24 Issue 2 Pg. 368-81 (Jan 26 2005) ISSN: 0261-4189 [Print] England
• PMID: 15635450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Nuclear Proteins
• Trans-Activators
• Transcription Factors
• Myeloid-Lymphoid Leukemia Protein
• Histone-Lysine N-Methyltransferase
• Kmt2a protein, mouse
• CREB-Binding Protein
• Crebbp protein, mouse

Topics

• Animals
• CREB-Binding Protein
• DNA-Binding Proteins (physiology)
• Histone-Lysine N-Methyltransferase
• Mice
• Molecular Sequence Data
• Myeloid-Lymphoid Leukemia Protein
• Myeloproliferative Disorders (chemically induced)
• Nuclear Proteins (physiology)
• Proto-Oncogenes (physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Trans-Activators (physiology)
• Transcription Factors (physiology)