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J. Biol. Chem., Vol. 279, Issue 19, 19471-19480, May 7, 2004

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Differential Regulatory and Compensatory Responses in Hematopoiesis/Erythropoiesis in - and -Globin Hemizygous Mice^*

Hugues Beauchemin, Marie-José Blouin, and Marie Trudel

From the Institut de Recherches Cliniques de Montréal, Molecular Genetics and Development, Faculte de Medecine de L'Universite de Montréal, Montréal, Québec H2W 1R7, Canada

Characterization of hematopoiesis/erythropoiesis in thalassemias from multipotent primitive cells to mature erythrocytes is of fundamental importance and clinical relevance. We investigated this process in - and -globin hemizygous mice, lacking the two adult tandemly organized genes from either the - or -globin locus. Although both mice backcrossed on a homogeneous background exhibited similar reduced red blood cell (RBC) survival, -globin hemizygous mice had less severe reticulocyte loss and globin chain imbalance, suggesting an apparently milder thalassemia than for -globin hemizygous mice. In contrast, however, -globin hemizygous mice displayed a more marked perturbation of hematologic parameters. Quantification of erythroid precursor subpopulations in marrow and spleen of -globin hemizygous mice showed more severely impaired maturation from the basophilic to orthochromatophilic erythroblasts and substantial loss of these late precursors probably as a consequence of a greater susceptibility to an excess of free -chain than -chain. Hence, only erythroid precursors exhibiting stochastically moderate chain imbalance would escape death and mature to reticulocyte/RBC stage, leading to survival and minimal loss of reticulocytes in the -globin hemizygous mice. Furthermore, in response to the ineffective erythropoiesis in -globin hemizygous mice, a dynamic compensatory hematopoiesis was observed at earlier differentiation stage as evidenced by a significant increase of erythroid progenitors (erythroid colony-forming units 100-fold) as well as of multipotent primitive cells (day 12 spleen colony-forming units 7-fold). This early compensatory mechanism was less pronounced in -globin hemizygous mice. The expansion of multipotent primitive and potentially stem cell populations, taken together with ineffective erythropoiesis and increased reticulocyte/RBC destruction could confer major cumulative advantage for gene targeting/bone marrow transplantation. Therefore, this study not only corroborated the strong potential effectiveness of transplantation for thalassemic hematopoietic therapy but also demonstrated the existence of a differential regulatory response for - and -thalassemia.

Received for publication, September 8, 2003 , and in revised form, February 13, 2004.

^* This work was supported by the Canadian Institute for Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of an Fonds de la Recherche en Santé du Québec studentship.

To whom correspondence should be addressed: Institut de Recherches Cliniques de Montréal, 110 Ouest Ave. des Pins, Montréal, Québec H2W 1R7, Canada. Tel.: 514-987-5712; Fax: 514-987-5585; E-mail: trudelm{at}IRCM.qc.ca.

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