Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes.

Normal human erythroid cell maturation requests the transcription factor GATA-1 and a transient activation of caspase-3, with GATA-1 being protected from caspase-3-mediated cleavage by interaction with the chaperone heat shock protein 70 (Hsp70) in the nucleus. Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA-1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70 family. GATA-1 protein expression is decreased in MDS erythroblasts, but restores in the presence of a pan-caspase inhibitor. Expression of a mutated GATA-1 that cannot be cleaved by caspase-3 rescues the transcription of GATA-1 targets, and the erythroid differentiation, but does not improve survival. Hsp70 fails to protect GATA-1 from caspases because the protein does not accumulate in the nucleus with active caspase-3. Expression of a nucleus-targeted mutant of Hsp70 protects GATA-1 and rescues MDS erythroid cell differentiation. Alteration of Hsp70 cytosolic-nuclear shuttling is a major feature of MDS that favors GATA-1 cleavage and differentiation impairment, but not apoptosis, in dysplastic erythroblasts.

[1]  J. Kutok,et al.  Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. , 2011, Blood.

[2]  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.

[3]  V. Viallon,et al.  p-ERK1/2 is a predictive factor of response to erythropoiesis-stimulating agents in low/int-1 myelodysplastic syndromes , 2010, Haematologica.

[4]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[5]  E. Solary,et al.  Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum , 2008, Leukemia.

[6]  Pablo Tamayo,et al.  An Erythroid Differentiation Signature Predicts Response to Lenalidomide in Myelodysplastic Syndrome , 2008, PLoS medicine.

[7]  T. Golub,et al.  Identification of RPS14 as a 5q- syndrome gene by RNA interference screen , 2007, Nature.

[8]  H. Beug,et al.  Acetylation and MAPK phosphorylation cooperate to regulate the degradation of active GATA-1. , 2007, The EMBO journal.

[9]  Olivier Hermine,et al.  Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1 , 2007, Nature.

[10]  G. Kroemer,et al.  Heat Shock Proteins 27 and 70: Anti-Apoptotic Proteins with Tumorigenic Properties , 2006, Cell cycle.

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

[12]  Giovanni Carlo Del Vecchio,et al.  Dyserythropoietic Anemia and Thrombocytopenia due to a Novel Mutation in GATA-1 , 2005, Acta Haematologica.

[13]  M. Cazzola,et al.  Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. , 2005, Blood.

[14]  C. Garrido,et al.  Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD. , 2005, Blood.

[15]  Masayuki Yamamoto,et al.  GATA1 Function, a Paradigm for Transcription Factors in Hematopoiesis , 2005, Molecular and Cellular Biology.

[16]  Hao Wang,et al.  Global regulation of erythroid gene expression by transcription factor GATA-1. , 2004, Blood.

[17]  M. Wiedmann,et al.  Caspase-3 has a nonapoptotic function in erythroid maturation. , 2004, Blood.

[18]  F. Tsukahara,et al.  Identification of Novel Nuclear Export and Nuclear Localization-related Signals in Human Heat Shock Cognate Protein 70* , 2004, Journal of Biological Chemistry.

[19]  Y. Hayashi,et al.  Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. , 2003, Blood.

[20]  J. Dupont,et al.  In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes : evidence for Fas-dependent apoptosis , 2002 .

[21]  U. Stochaj,et al.  Heat‐induced nuclear accumulation of hsc70 proteins is regulated by phosphorylation and inhibited in confluent cells , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Olivier Hermine,et al.  Caspase Activation Is Required for Terminal Erythroid Differentiation , 2001, The Journal of experimental medicine.

[23]  S. Orkin,et al.  Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1 , 2000, Nature Genetics.

[24]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[25]  S. Srinivasula,et al.  Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1 , 1999, Nature.

[26]  H. Lodish,et al.  Fetal Anemia and Apoptosis of Red Cell Progenitors in Stat5a−/−5b−/− Mice A Direct Role for Stat5 in Bcl-XL Induction , 1999, Cell.

[27]  S. Orkin,et al.  GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. , 1999, Blood.

[28]  S. Orkin,et al.  Consequences of GATA-1 Deficiency in Megakaryocytes and Platelets , 1999 .

[29]  Y Fujiwara,et al.  Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Orkin,et al.  Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1 , 1991, Nature.

[31]  N. Nadal,et al.  Expression and prognostic significance of heat-shock proteins in myelodysplastic syndromes. , 2006, Haematologica.

[32]  P. Greenberg,et al.  Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. , 1996, Blood.