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Brief Definitive Report |
Correspondence to: Warren S. Pear, 611 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160. Tel:215-573-7764 Fax:215-573-8606 E-mail:wpear{at}mail.med.upenn.edu.
Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2-/-) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)-/- mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2-/- progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3
and pre-T
mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2-/- mice with a TCRß transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes.
Key Words: leukemia, development, hematopoiesis, lymphocyte, stem cells
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