Prdm16 is a physiologic regulator of hematopoietic stem cells.

Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

[1]  S. Nimer,et al.  The p53 tumor suppressor protein regulates hematopoietic stem cell fate , 2011, Journal of cellular physiology.

[2]  B. Levi,et al.  Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress , 2010, Nature Cell Biology.

[3]  A. Look,et al.  Deletion of proapoptotic Puma selectively protects hematopoietic stem and progenitor cells against high-dose radiation. , 2010, Blood.

[4]  L. Fradkin,et al.  Ryks: new partners for Wnts in the developing and regenerating nervous system , 2010, Trends in Neurosciences.

[5]  T. Suda,et al.  Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells. , 2010, Experimental hematology.

[6]  Joshua M. Stuart,et al.  Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells , 2010, PloS one.

[7]  In Hye Lee,et al.  Bmi1 regulates mitochondrial function and the DNA damage response pathway , 2009, Nature.

[8]  Frank J T Staal,et al.  Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation. , 2009, Blood.

[9]  Y. Liu,et al.  p53 regulates hematopoietic stem cell quiescence. , 2009, Cell stem cell.

[10]  Nathan C Boles,et al.  Mouse hematopoietic stem cell identification and analysis , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[11]  Jian Yu,et al.  Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose gamma-irradiation. , 2008, Blood.

[12]  G. Sauvageau,et al.  A Functional Screen to Identify Novel Effectors of Hematopoietic Stem Cell Activity , 2008, Cell.

[13]  B. Spiegelman,et al.  PRDM16 controls a brown fat/skeletal muscle switch , 2008, Nature.

[14]  S. Ogawa,et al.  Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. , 2008, Cell stem cell.

[15]  Mark J. Murphy,et al.  Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. , 2008, Cell stem cell.

[16]  P. Vogt,et al.  The Bax Inhibitor-1 (BI-1) family in apoptosis and tumorigenesis. , 2008, Current molecular medicine.

[17]  L. Zon,et al.  Hematopoiesis: An Evolving Paradigm for Stem Cell Biology , 2008, Cell.

[18]  S. Minucci,et al.  Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice. , 2007, The Journal of clinical investigation.

[19]  C. Preudhomme,et al.  RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. , 2007, Blood.

[20]  J. Fisher,et al.  Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. , 2007, Cell stem cell.

[21]  D. Kioussis,et al.  Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. , 2007, Cell stem cell.

[22]  R. Hardy,et al.  The protean nature of cells in the B lymphocyte lineage. , 2007, Immunity.

[23]  A. Iwama,et al.  Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice , 2006, The Journal of experimental medicine.

[24]  S. Morrison,et al.  Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. , 2006, Blood.

[25]  W. Vainchenker,et al.  Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4-/- chimeric mice. , 2006, Blood.

[26]  Yan Liu,et al.  The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. , 2006, Cancer cell.

[27]  N. Copeland,et al.  Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. , 2005, Blood.

[28]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[29]  J. Aster,et al.  Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. , 2005, Cell stem cell.

[30]  S. Fujita,et al.  Novel RUNX1‐PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22) , 2005, Genes, chromosomes & cancer.

[31]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[32]  Keisuke Ito,et al.  Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche , 2004, Cell.

[33]  S. Korsmeyer,et al.  Definitive hematopoiesis requires the mixed-lineage leukemia gene. , 2004, Developmental cell.

[34]  H. Snoeck,et al.  Quantitative Trait Analysis Reveals Transforming Growth Factor-β2 as a Positive Regulator of Early Hematopoietic Progenitor and Stem Cell Function , 2004, The Journal of experimental medicine.

[35]  Peter Vogel,et al.  Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Takuro Nakamura,et al.  A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. , 2003, Blood.

[37]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[38]  A. Bhandoola,et al.  Thymopoiesis independent of common lymphoid progenitors , 2003, Nature Immunology.

[39]  R. Frederickson,et al.  Fluidigm. Biochips get indoor plumbing. , 2002, Chemistry & biology.

[40]  S. Matsuoka,et al.  CD34 expression on long-term repopulating hematopoietic stem cells changes during developmental stages. , 2001, Blood.

[41]  D. Scadden,et al.  Stem cell repopulation efficiency but not pool size is governed by p27kip1 , 2000, Nature Medicine.

[42]  D. Scadden,et al.  Hematopoietic stem cell quiescence maintained by p21cip1/waf1. , 2000, Science.

[43]  A. Murray,et al.  Association of Spindle Assembly Checkpoint Component XMAD2 with Unattached Kinetochores , 1996, Science.

[44]  Hiromitsu Nakauchi,et al.  Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell , 1996, Science.

[45]  M. Marín‐Padilla,et al.  Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[46]  J. Downing,et al.  AML1, the Target of Multiple Chromosomal Translocations in Human Leukemia, Is Essential for Normal Fetal Liver Hematopoiesis , 1996, Cell.

[47]  C. Begley,et al.  Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Orkin,et al.  Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL , 1995, Nature.

[49]  Stuart H. Orkin,et al.  An early haematopoietic defect in mice lacking the transcription factor GATA-2 , 1994, Nature.

[50]  A. Zlotnik,et al.  A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. , 1993, Journal of immunology.

[51]  Carmen Domingo.  Biology , 1929, Nature.

[52]  H. Snoeck,et al.  Identification and in vivo analysis of murine hematopoietic stem cells. , 2010, Methods in enzymology.

[53]  B. Spiegelman,et al.  Initiation of myoblast to brown fat switch by a PRDM 16 – C / EBP-b transcriptional complex , 2009 .

[54]  J. Yokota,et al.  A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. , 2000, Blood.