Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
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.
Wang
Jing
J
Department of Pathology and Medicine, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Iwasaki
Hiromi
H
Krivtsov
Andrei
A
Febbo
Phillip G
PG
Thorner
Aaron R
AR
Ernst
Patricia
P
Anastasiadou
Ema
E
Kutok
Jeffery L
JL
Kogan
Scott C
SC
Zinkel
Sandra S
SS
Fisher
Jill K
JK
Hess
Jay L
JL
Golub
Todd R
TR
Armstrong
Scott A
SA
Akashi
Koichi
K
Korsmeyer
Stanley J
SJ
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*
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