MLF1IP promotes normal erythroid proliferation and is involved in the pathogenesis of polycythemia vera

Myelodysplasia/myeloid leukemia factor 1‐interacting protein (MLF1IP) appears to be an erythroid lineage‐specific gene in mice; however, its role in normal erythropoiesis and erythropoietic disorders have not yet been elucidated. Here, we found that MLF1IP is abundantly expressed in human erythroid progenitor cells and that MLF1IP‐deficiency reduces cell proliferation resulting from cell cycle arrest. Moreover, MLF1IP expression is exclusively elevated in CFU‐E cells from polycythemia vera (PV) patients, and MLF1IP transgenic mice develop a PV‐like disorder. Further analyses revealed that the erythroid progenitors and early‐stage erythroblasts from these transgenic mice expand by up‐regulating cyclin D2 and down‐regulating p27 and p21. Thus, our data demonstrate that MLF1IP promotes erythroid proliferation and is involved in the pathogenesis of PV, suggesting that it might be a novel molecular target for erythropoietic disorders.

[1]  Jie Li,et al.  Global transcriptome analyses of human and murine terminal erythroid differentiation. , 2014, Blood.

[2]  E. Solary,et al.  JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα. , 2013, Blood.

[3]  S. Verstovsek,et al.  Investigational Janus kinase inhibitors , 2013, Expert opinion on investigational drugs.

[4]  N. Taylor,et al.  Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo. , 2013, Blood.

[5]  F. Passamonti.  How I treat polycythemia vera. , 2012, Blood.

[6]  R. Gale,et al.  Unique features of primary myelofibrosis in Chinese. , 2012, Blood.

[7]  Kyung S. Lee,et al.  Feed-forward mechanism of converting biochemical cooperativity to mitotic processes at the kinetochore plate , 2011, Proceedings of the National Academy of Sciences.

[8]  M. Griesshammer,et al.  Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Yuejia Huang,et al.  CENP-U Cooperates with Hec1 to Orchestrate Kinetochore-Microtubule Attachment* , 2010, The Journal of Biological Chemistry.

[10]  P. Guglielmelli,et al.  Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal , 2008, Leukemia.

[11]  W. Vainchenker,et al.  The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. , 2007, Blood.

[12]  E. Susaki,et al.  Cyclin D2 Translocates p27 out of the Nucleus and Promotes Its Degradation at the G0-G1 Transition , 2007, Molecular and Cellular Biology.

[13]  H. Kimura,et al.  The Constitutive Centromere Component CENP-50 Is Required for Recovery from Spindle Damage , 2005, Molecular and Cellular Biology.

[14]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[15]  J. Prchal.  Polycythemia vera and other primary polycythemias , 2005, Current opinion in hematology.

[16]  J. Thiele,et al.  Diagnostic impact of bone marrow histopathology in polycythemia vera (PV). , 2005, Histology and histopathology.

[17]  S. E. Jacobsen,et al.  Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation. , 2004, Blood.

[18]  Erich A. Nigg,et al.  Polo-like kinases and the orchestration of cell division , 2004, Nature Reviews Molecular Cell Biology.

[19]  Xiaoping Du,et al.  cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP , 2004, Oncogene.

[20]  F. Girodon,et al.  Standardization and comparison of endogenous erythroid colony assays performed with bone marrow or blood progenitors for the diagnosis of polycythemia vera. , 2004, The hematology journal : the official journal of the European Haematology Association.

[21]  F. Girodon,et al.  Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. , 2004, Haematologica.

[22]  Shou-Jiang Gao,et al.  Identification of a Novel Cellular Transcriptional Repressor Interacting with the Latent Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus , 2003, Journal of Virology.

[23]  D. Scadden,et al.  Ex vivo targeting of p21Cip1/Waf1 permits relative expansion of human hematopoietic stem cells. , 2003, Blood.

[24]  S. Collins,et al.  IL-3-induced enhancement of retinoic acid receptor activity is mediated through Stat5, which physically associates with retinoic acid receptors in an IL-3-dependent manner. , 2002, Blood.

[25]  J. Spivak,et al.  Polycythemia vera: myths, mechanisms, and management. , 2002, Blood.

[26]  M. Dai,et al.  An expansion phase precedes terminal erythroid differentiation of hematopoietic progenitor cells from cord blood in vitro and is associated with up-regulation of cyclin E and cyclin-dependent kinase 2. , 2000, Blood.

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

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

[29]  A. W. Harris,et al.  Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment. , 1999, Blood.

[30]  L. Hennighausen,et al.  Stimulation of Stat5 by granulocyte colony-stimulating factor (G-CSF) is modulated by two distinct cytoplasmic regions of the G-CSF receptor. , 1998, Journal of immunology.

[31]  M. Roussel,et al.  Rescue of defective mitogenic signaling by D-type cyclins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Levy,et al.  Thrombopoietin activates a STAT5‐like factor in hematopoietic cells. , 1995, The EMBO journal.

[33]  A. Miyajima,et al.  Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. , 1995, The EMBO journal.

[34]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[35]  S. Shurtleff,et al.  Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. , 1993, Genes & development.

[36]  G. Birgegard,et al.  Serum erythropoietin in the diagnosis of polycythaemia and after phlebotomy treatment , 1992, British journal of haematology.

[37]  A. Eaves,et al.  Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties. , 1978, Blood.

[38]  A. Eaves,et al.  Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses. , 1977, Blood.

[39]  J. Fisher,et al.  Effects of testosterone and erythropoietin on erythroid colony formation in human bone marrow cultures. , 1975, Blood.

[40]  A. Axelrad,et al.  Improved plasma culture system for production of erythrocytic colonies in vitro: quantitative assay method for CFU-E. , 1974, Blood.

[41]  F. Sieber,et al.  Erythroid colony formation in cultures of mouse and human bone marrow: Analysis of the requirement for erythropoietin by gel filtration and affinity chromatography on agarose‐concanavalin A , 1974, Journal of cellular physiology.

[42]  J. Stephenson,et al.  Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Scadden,et al.  Hematopoietic Stem Cell Quiescence Maintained by p 21 cip 1 / waf 1 , 2022 .