Chelsia Qiuxia Wang1,2,7, Desmond Wai Loon Chin1,7, Jing Yuan Chooi1,7, Chng Wee Joo1, Ichiro Taniuchi3, Vinay Tergaonkar2*, Motomi Osato1,7.*
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore;
2 Institute of Molecular and Cell Biology, Singapore;
3 RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
4 Institute of Bioengineering and Nanotechnology, Singapore
7 These authors contributed equally to this work.
*Corresponding Authors: Vinay Tergaonkar, firstname.lastname@example.org, Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore 138673. Tel: +65-6601-1442. Fax: +65-6873-9664.
Motomi Osato, MD, email@example.com, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599,
Published in Leukemia, 5 November 2014; doi: 10.1038/leu.2014.316
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The PEBP2/CBF heterodimeric transcription factors consist of two subunits: a DNA-binding α subunit (Runx1, Runx2 or Runx3) and a non-DNA-binding β subunit (PEBP2b/Cbfβ) encoded by Cbfb. RUNX1 and CBFB play critical roles in hematopoiesis and are frequently mutated in human leukemia. Similar to Runx1-/- mice, Cbfb-/- embryos die at midgestation due to hemorrhage and complete lack of hematopoietic stem cells (HSCs). Due to this embryonic lethality, Cbfb function in adult hematopoiesis remains unknown. Here, we show that Cbfb conditional knockout (cKO) mice exhibited differentiation blockages and HSC expansion that are more drastic than Runx1 cKO mice. Notably, such precancerous status was more pronounced when Cbfb was inactivated at neonatal stage by using Vav-iCre system, as compared to that at adult stage by Mx-Cre system. This age-dependent phenotypic enhancement may underlie the high prevalence of human RUNX leukemia in childhood and younger adults.
Figure Legend: Schematic diagram showing hematological phenotypes in Cbfb cKO mice.
(A) Differentiation blocks (lines) at specific developmental stages in multiple lineages and resultant relative increase of immediate upstream population (arrows) in the Cbfb cKO mice are shown. The size of arrow represents the magnitude of changes. The differentiation blocks led to the failure in production of mature cells of various lineages (arrows within yellow box). Changes in the HSPC compartments are also indicated (arrows). Blue, Cbfbfl/fl;Mx1-Cre+; red, Cbfbfl/fl;Vav-iCre+; green, Cbfb cKO.
Diagram showing the window within which Cbfb is indispensable at the developmental stage and within which Cbfb is dispensable at the adult stage. Top, cell cycle status of HSCs is indicated. Bottom, the time when Vav-iCre or Mx1-Cre are expressed in hematopoietic tissues are depicted.
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