Expression of the runt homology domain of RUNX1 disrupts homeostasis of hematopoietic stem cells and induces progression to myelodysplastic syndrome.

Mutations of RUNX1 are detected in patients with myelodysplastic syndrome (MDS). In particular, C-terminal truncation mutations lack a transcription regulatory domain and have increased DNA binding through the runt homology domain. The expression of the runt homology domain, RUNX1(41-214), in mouse hematopoietic cells induced progression to MDS and acute myeloid leukemia. Analysis of premyelodysplastic animals found expansion of c-Kit(+)Sca-1(+)Lin(-) cells and skewed differentiation to myeloid at the expense of the lymphoid lineage. These abnormalities correlate with the phenotype of Runx1-deficient animals, as expected given the reported dominant-negative role of C-terminal mutations over the full-length RUNX1. However, MDS is not observed in Runx1-deficient animals. Gene expression profiling found that RUNX1(41-214) c-Kit(+)Sca-1(+)Lin(-) cells have an overlapping yet distinct gene expression profile from Runx1-deficient animals. Moreover, an unexpected parallel was observed between the hematopoietic phenotype of RUNX1(41-214) and aged animals. Genes deregulated in RUNX1(41-214), but not in Runx1-deficient animals, were inversely correlated with the aging gene signature of HSCs, suggesting that disruption of the expression of genes related to normal aging by RUNX1 mutations contributes to development of MDS. The data presented here provide insights into the mechanisms of development of MDS in HSCs by C-terminal mutations of RUNX1.

[1]  J. Gaudet,et al.  Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells , 2011, PloS one.

[2]  M. Sigvardsson,et al.  Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. , 2011, Cell stem cell.

[3]  Eva Budinska,et al.  A distinct expression of various gene subsets in CD34+ cells from patients with early and advanced myelodysplastic syndrome. , 2010, Leukemia research.

[4]  M. Sekeres The epidemiology of myelodysplastic syndromes. , 2010, Hematology/oncology clinics of North America.

[5]  Nathan C Boles,et al.  Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. , 2010, Cell stem cell.

[6]  S. Anderson,et al.  Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11. , 2010, Blood.

[7]  M. Cazzola,et al.  Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells. , 2009 .

[8]  S. K. Zaidi,et al.  Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. , 2009, Blood.

[9]  D. Liang,et al.  RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation , 2009, Leukemia.

[10]  H. Otu,et al.  Differential gene expression of bone marrow-derived CD34+ cells is associated with survival of patients suffering from myelodysplastic syndrome , 2009, International journal of hematology.

[11]  Elaine Dzierzak,et al.  Runx1 is required for the endothelial to hematopoietic cell transition but not thereafter , 2009, Nature.

[12]  E. Venturini,et al.  AML1/ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets , 2008, PLoS genetics.

[13]  D. Birnbaum,et al.  Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes , 2008, BMC Cancer.

[14]  S. Cheng,et al.  Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia. , 2008, Blood.

[15]  R. Ono,et al.  AML1 mutations induced MDS and MDS/AML in a mouse BMT model. , 2008, Blood.

[16]  S. Ofori-Acquah,et al.  Activated leukocyte cell adhesion molecule: a new paradox in cancer. , 2008, Translational research : the journal of laboratory and clinical medicine.

[17]  D. Scadden,et al.  Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation , 2008, Nature Reviews Genetics.

[18]  D. Littman,et al.  Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis. , 2007, Blood.

[19]  K. Mills,et al.  Transcriptional dysregulation mediated by RUNX1-RUNX1T1 in normal human progenitor cells and in acute myeloid leukaemia , 2007, Leukemia.

[20]  J. Gaudet,et al.  Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity. , 2007, Cancer cell.

[21]  S. Tsuzuki,et al.  Isoform-Specific Potentiation of Stem and Progenitor Cell Engraftment by AML1/RUNX1 , 2007, PLoS medicine.

[22]  M. Kitagawa,et al.  Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia , 2007, British journal of haematology.

[23]  Guoqiang Chen,et al.  Leukemogenic AML1‐ETO fusion protein upregulates expression of connexin 43: The role in AML1‐ETO‐induced growth arrest in leukemic cells , 2006, Journal of cellular physiology.

[24]  Li Wang,et al.  Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype. , 2006, Blood.

[25]  F. Buchholz,et al.  AML1 deletion in adult mice causes splenomegaly and lymphomas , 2006, Oncogene.

[26]  S. Morrison,et al.  SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. , 2006, Blood.

[27]  P. Vyas,et al.  Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome. , 2005, Blood.

[28]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Zhenhua Zhang,et al.  NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. , 2005, Blood.

[30]  I. Weissman,et al.  Cell intrinsic alterations underlie hematopoietic stem cell aging. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Kajigaya,et al.  Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. , 2004, Blood.

[32]  J. Kutok,et al.  Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. , 2004, Blood.

[33]  T. Kyo,et al.  High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. , 2004, Blood.

[34]  H Phillip Koeffler,et al.  Myelodysplastic Bone Marrow Cells from Normal and + Characterization of Gene Expression of Cd34 , 2002 .

[35]  I. Petit,et al.  Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. , 2002, Experimental hematology.

[36]  J. Downing,et al.  Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. , 2002, Blood.

[37]  A. Friedman,et al.  AML1 stimulates G1 to S progression via its transactivation domain , 2002, Oncogene.

[38]  Cheng Li,et al.  Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application , 2001, Genome Biology.

[39]  H. Nakauchi,et al.  Age-Associated Characteristics of Murine Hematopoietic Stem Cells , 2000, The Journal of experimental medicine.

[40]  E. Macintyre,et al.  High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2αB gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21 , 2000 .

[41]  T. Gu,et al.  Auto-Inhibition and Partner Proteins, Core-Binding Factor β (CBFβ) and Ets-1, Modulate DNA Binding by CBFα2 (AML1) , 2000, Molecular and Cellular Biology.

[42]  John M. Maris,et al.  Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia , 1999, Nature Genetics.

[43]  H. Yamasaki,et al.  Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. , 1999, Blood.

[44]  J. Zhang,et al.  The AML1/ETO fusion protein activates transcription of BCL-2. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[45]  I. Weissman,et al.  The aging of hematopoietic stem cells , 1996, Nature Medicine.

[46]  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.

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

[48]  S. Ogawa,et al.  This information is current as Hematopoiesis Hematopoietic Stem Cells in Adult AML 1 / Runx 1 Negatively Regulates Quiescent , 2008 .

[49]  V. Band,et al.  Shared as well as distinct roles of EHD proteins revealed by biochemical and functional comparisons in mammalian cells and C. elegans. , 2007, BMC cell biology.

[50]  Edward H. Cho,et al.  Hemostasis, Thrombosis, and Vascular Biology Materials and Methods Cell Culture and Transfection , 2022 .

[51]  E. Macintyre,et al.  High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. , 2000, Blood.