title: 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.affiliation: Department of Pathology and Medicine, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Andrei
authors.initials: A
authors.lastname: Krivtsov
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Febbo
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.forename: Ema
authors.initials: E
authors.lastname: Anastasiadou
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Zinkel
authors.forename: Jill K
authors.initials: JK
authors.lastname: Fisher
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D051379:Mice; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009196:Myeloproliferative Disorders / Q000139:chemically induced*; D009687:Nuclear Proteins / Q000502:physiology*; D011519:Proto-Oncogenes / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse