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Functional but Abnormal Adult Erythropoiesis in the Absence of the Stem Cell Leukemia Gene

Mark A. Hall,^1, Nicholas J. Slater,¹ C. Glenn Begley,² Jessica M. Salmon,¹ Leonie J. Van Stekelenburg,¹ Matthew P. McCormack,¹ Stephen M. Jane,¹ and David J. Curtis^1*

Rotary Bone Marrow Research Laboratories, P.O. Box Royal Melbourne Hospital, Grattan St., Melbourne 3050, Australia,¹ Amgen, One Amgen Center Drive, Thousand Oaks, California 91320-1799²

Received 20 December 2004/ Returned for modification 5 February 2005/ Accepted 8 May 2005

Previous studies have indicated that the stem cell leukemia gene (SCL) is essential for both embryonic and adult erythropoiesis. We have examined erythropoiesis in conditional SCL knockout mice for at least 6 months after loss of SCL function and report that SCL was important but not essential for the generation of mature red blood cells. Although SCL-deleted mice were mildly anemic with increased splenic erythropoiesis, they responded appropriately to endogenous erythropoietin and hemolytic stress, a measure of late erythroid progenitors. However, SCL was more important for the proliferation of early erythroid progenitors because the predominant defects in SCL-deleted erythropoiesis were loss of in vitro growth of the burst-forming erythroid unit and an in vivo growth defect revealed by transplant assays. With respect to erythroid maturation, SCL-deleted proerythroblasts could generate more mature erythroblasts and circulating red blood cells. However, SCL was required for normal expression of TER119, one of the few proposed target genes of SCL. The unexpected finding that SCL-independent erythropoiesis can proceed in the adult suggests that alternate factors can replace the essential functions of SCL and raises the possibility that similar mechanisms also explain the relatively minor defects previously observed in SCL-null hematopoietic stem cells.

Present address: St. Jude Children's Research Hospital, Memphis, TN.

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