Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11.
It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression-independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11(+) leukemia samples. Interestingly, Cbfb-MYH11(+) preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb(+). Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression-independent activities contribute to leukemogenesis by Cbfb-MYH11.
Hyde
R Katherine
RK
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Kamikubo
Yasuhiko
Y
Anderson
Stacie
S
Kirby
Martha
M
Alemu
Lemlem
L
Zhao
Ling
L
Liu
P Paul
PP
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D015415:Biomarkers; C095514:CBFbeta-MYH11 fusion protein; D050676:Core Binding Factor Alpha 2 Subunit; D053648:Cytokine Receptor Common beta Subunit; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D015514:Oncogene Proteins, Fusion; D011956:Receptors, Cell Surface; C493726:Runx1 protein, mouse; C072186:Csf2rb protein, mouse