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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3261-3273

HEMATOPOIESIS

Ineffective erythropoiesis in Stat5aminus /minus 5bminus /minus mice due to decreased survival of early erythroblasts

Merav Socolovsky, Hyung-song Nam, Mark D. Fleming, Volker H. Haase, Carlo Brugnara, and Harvey F. Lodish

From the Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA; Department of Pathology, Children's Hospital; Department of Laboratory Medicine, Children's Hospital, Harvard Medical School; Renal Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Erythropoietin (Epo) controls red cell production in the basal state and during stress. Epo binding to its receptor, EpoR, on erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal liver erythroid progenitors were found in Stat5a-/-5b-/- mice. However, the role of Stat5 in adult erythropoiesis was not clear. The present study shows that some adult Stat5a-/-5b-/- mice have a near-normal hematocrit but are deficient in generating high erythropoietic rates in response to stress. Further, many adult Stat5a-/-5b-/- mice have persistent anemia despite a marked compensatory expansion in their erythropoietic tissue. Analysis of erythroblast maturation in Stat5a-/-5b-/- hematopoietic tissue shows a dramatic increase in early erythroblast numbers, but these fail to progress in differentiation. Decreased expression of bcl-xL and increased apoptosis in Stat5a-/-5b-/- early erythroblasts correlate with the degree of anemia. Hence, Stat5 controls a rate-determining step regulating early erythroblast survival.

© 2001 by The American Society of Hematology.
 

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M. P. Menon, J. Fang, and D. M. Wojchowski
Core erythropoietin receptor signals for late erythroblast development
Blood, April 1, 2006; 107(7): 2662 - 2672.
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J. Biol. Chem.Home page
M. Um and H. F. Lodish
Antiapoptotic Effects of Erythropoietin in Differentiated Neuroblastoma SH-SY5Y Cells Require Activation of Both the STAT5 and AKT Signaling Pathways
J. Biol. Chem., March 3, 2006; 281(9): 5648 - 5656.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
A. D. Patterson, M. C. Hollander, G. F. Miller, and A. J. Fornace Jr.
Gadd34 requirement for normal hemoglobin synthesis.
Mol. Cell. Biol., March 1, 2006; 26(5): 1644 - 1653.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
J. F. Langenheim, D. Tan, A. M. Walker, and W. Y. Chen
Two Wrongs Can Make a Right: Dimers of Prolactin and Growth Hormone Receptor Antagonists Behave as Agonists
Mol. Endocrinol., March 1, 2006; 20(3): 661 - 674.
[Abstract] [Full Text] [PDF]


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BloodHome page
K. Kitajima, M. Tanaka, J. Zheng, H. Yen, A. Sato, D. Sugiyama, H. Umehara, E. Sakai, and T. Nakano
Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2
Blood, March 1, 2006; 107(5): 1857 - 1863.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
M. Sanchez, I. L. Weissman, M. Pallavicini, M. Valeri, P. Guglielmelli, A. M. Vannucchi, G. Migliaccio, and A. R. Migliaccio
Differential Amplification of Murine Bipotent Megakaryocytic/Erythroid Progenitor and Precursor Cells During Recovery from Acute and Chronic Erythroid Stress
Stem Cells, February 1, 2006; 24(2): 337 - 348.
[Abstract] [Full Text] [PDF]


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JCBHome page
J. M. Brown, J. Leach, J. E. Reittie, A. Atzberger, J. Lee-Prudhoe, W. G. Wood, D. R. Higgs, F. J. Iborra, and V. J. Buckle
Coregulated human globin genes are frequently in spatial proximity when active
J. Cell Biol., January 17, 2006; 172(2): 177 - 187.
[Abstract] [Full Text] [PDF]


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BloodHome page
J. Zheng, K. Kitajima, E. Sakai, T. Kimura, N. Minegishi, M. Yamamoto, and T. Nakano
Differential effects of GATA-1 on proliferation and differentiation of erythroid lineage cells
Blood, January 15, 2006; 107(2): 520 - 527.
[Abstract] [Full Text] [PDF]


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BloodHome page
T. Ishikawa-Sekigami, Y. Kaneko, H. Okazawa, T. Tomizawa, J. Okajo, Y. Saito, C. Okuzawa, M. Sugawara-Yokoo, U. Nishiyama, H. Ohnishi, et al.
SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages
Blood, January 1, 2006; 107(1): 341 - 348.
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BloodHome page
F. Martelli, B. Ghinassi, B. Panetta, E. Alfani, V. Gatta, A. Pancrazzi, C. Bogani, A. M. Vannucchi, F. Paoletti, G. Migliaccio, et al.
Variegation of the phenotype induced by the Gata1low mutation in mice of different genetic backgrounds
Blood, December 15, 2005; 106(13): 4102 - 4113.
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BloodHome page
C. J. Wu, L. Krishnamurti, J. L. Kutok, M. Biernacki, S. Rogers, W. Zhang, J. H. Antin, and J. Ritz
Evidence for ineffective erythropoiesis in severe sickle cell disease
Blood, November 15, 2005; 106(10): 3639 - 3645.
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Stem CellsHome page
L. Silberstein, M.-J. Sanchez, M. Socolovsky, Y. Liu, G. Hoffman, S. Kinston, S. Piltz, M. Bowen, L. Gambardella, A. R. Green, et al.
Transgenic Analysis of the Stem Cell Leukemia +19 Stem Cell Enhancer in Adult and Embryonic Hematopoietic and Endothelial Cells
Stem Cells, September 1, 2005; 23(9): 1378 - 1388.
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BloodHome page
M. M. Rhodes, P. Kopsombut, M. C. Bondurant, J. O. Price, and M. J. Koury
Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin
Blood, September 1, 2005; 106(5): 1857 - 1863.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
M. A. Hall, N. J. Slater, C. G. Begley, J. M. Salmon, L. J. Van Stekelenburg, M. P. McCormack, S. M. Jane, and D. J. Curtis
Functional but Abnormal Adult Erythropoiesis in the Absence of the Stem Cell Leukemia Gene
Mol. Cell. Biol., August 1, 2005; 25(15): 6355 - 6362.
[Abstract] [Full Text] [PDF]


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Mol. Interv.Home page
M. Pesu, J. O'Shea, L. Hennighausen, and O. Silvennoinen
Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders
Mol. Interv., August 1, 2005; 5(4): 211 - 215.
[Abstract] [Full Text] [PDF]


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BloodHome page
W. Tong, J. Zhang, and H. F. Lodish
Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways
Blood, June 15, 2005; 105(12): 4604 - 4612.
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BloodHome page
R. Doyonnas, J. S. Nielsen, S. Chelliah, E. Drew, T. Hara, A. Miyajima, and K. M. McNagny
Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells
Blood, June 1, 2005; 105(11): 4170 - 4178.
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DevelopmentHome page
C. Angelin-Duclos, C. Domenget, A. Kolbus, H. Beug, P. Jurdic, and J. Samarut
Thyroid hormone T3 acting through the thyroid hormone {alpha} receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse
Development, March 1, 2005; 132(5): 925 - 934.
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BloodHome page
G. Terszowski, C. Waskow, P. Conradt, D. Lenze, J. Koenigsmann, D. Carstanjen, I. Horak, and H.-R. Rodewald
Prospective isolation and global gene expression analysis of the erythrocyte colony-forming unit (CFU-E)
Blood, March 1, 2005; 105(5): 1937 - 1945.
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Stem CellsHome page
A. L. Drayer, A.-K. Boer, E. L. Los, M. T. Esselink, and E. Vellenga
Stem Cell Factor Synergistically Enhances Thrombopoietin-Induced STAT5 Signaling in Megakaryocyte Progenitors through JAK2 and Src Kinase
Stem Cells, February 1, 2005; 23(2): 240 - 251.
[Abstract] [Full Text] [PDF]


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BloodHome page
A. Halupa, M. L. Bailey, K. Huang, N. N. Iscove, D. E. Levy, and D. L. Barber
A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution
Blood, January 15, 2005; 105(2): 552 - 561.
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GENES CELLSHome page
M. Nakano, K. Ohneda, H. Yamamoto-Mukai, R. Shimizu, O. Ohneda, S. Ohmura, M. Suzuki, S. Tsukamoto, T. Yanagawa, H. Yoshida, et al.
Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells
Genes Cells, January 1, 2005; 10(1): 47 - 62.
[Abstract] [Full Text] [PDF]


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BloodHome page
K. W. Harder, C. Quilici, E. Naik, M. Inglese, N. Kountouri, A. Turner, K. Zlatic, D. M. Tarlinton, and M. L. Hibbs
Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1
Blood, December 15, 2004; 104(13): 3901 - 3910.
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BloodHome page
Y. Nakano, S. Imagawa, K. Matsumoto, C. Stockmann, N. Obara, N. Suzuki, T. Doi, T. Kodama, S. Takahashi, T. Nagasawa, et al.
Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease
Blood, December 15, 2004; 104(13): 4300 - 4307.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
J. J. Schuringa, K. Wu, G. Morrone, and M. A.S. Moore
Enforced Activation of STAT5A Facilitates the Generation of Embryonic Stem-Derived Hematopoietic Stem Cells That Contribute to Hematopoiesis In Vivo
Stem Cells, December 1, 2004; 22(7): 1191 - 1204.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
Y. Cui, G. Riedlinger, K. Miyoshi, W. Tang, C. Li, C.-X. Deng, G. W. Robinson, and L. Hennighausen
Inactivation of Stat5 in Mouse Mammary Epithelium during Pregnancy Reveals Distinct Functions in Cell Proliferation, Survival, and Differentiation
Mol. Cell. Biol., September 15, 2004; 24(18): 8037 - 8047.
[Abstract] [Full Text] [PDF]


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BloodHome page
C. Waskow, G. Terszowski, C. Costa, M. Gassmann, and H.-R. Rodewald
Rescue of lethal c-KitW/W mice by erythropoietin
Blood, September 15, 2004; 104(6): 1688 - 1695.
[Abstract] [Full Text] [PDF]


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JEMHome page
J. J. Schuringa, K. Y. Chung, G. Morrone, and M. A.S. Moore
Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation
J. Exp. Med., September 7, 2004; 200(5): 623 - 635.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson
Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation
J. Immunol., September 1, 2004; 173(5): 3131 - 3139.
[Abstract] [Full Text] [PDF]


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BloodHome page
S. M. Jacobs-Helber and S. T. Sawyer
Jun N-terminal kinase promotes proliferation of immature erythroid cells and erythropoietin-dependent cell lines
Blood, August 1, 2004; 104(3): 696 - 703.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
W. Zhou, Q. Zhao, R. Sutton, H. Cumming, X. Wang, L. Cerruti, M. Hall, R. Wu, J. M. Cunningham, and S. M. Jane
The Role of p22 NF-E4 in Human Globin Gene Switching
J. Biol. Chem., June 18, 2004; 279(25): 26227 - 26232.
[Abstract] [Full Text] [PDF]


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BloodHome page
E. van den Akker, T. van Dijk, M. Parren-van Amelsvoort, K. S. Grossmann, U. Schaeper, K. Toney-Earley, S. E. Waltz, B. Lowenberg, and M. von Lindern
Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors
Blood, June 15, 2004; 103(12): 4457 - 4465.
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BloodHome page
K.-H. Chang, M. Tam, and M. M. Stevenson
Inappropriately low reticulocytosis in severe malarial anemia correlates with suppression in the development of late erythroid precursors
Blood, May 15, 2004; 103(10): 3727 - 3735.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
H. Beauchemin, M.-J. Blouin, and M. Trudel
Differential Regulatory and Compensatory Responses in Hematopoiesis/Erythropoiesis in {alpha}- and {beta}-Globin Hemizygous Mice
J. Biol. Chem., May 7, 2004; 279(19): 19471 - 19480.
[Abstract] [Full Text] [PDF]



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