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Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells 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 CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2 −/ − mice with a TCRβ 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. leukemia development hematopoiesis lymphocyte stem cells Footnotes Submitted: 5 February 2001 Revision requested 1 May 2001 Accepted: 24 May 2001 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

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References (38)

Publisher
Rockefeller University Press
Copyright
© 2001 The Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.194.1.99
Publisher site
See Article on Publisher Site

Abstract

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 CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2 −/ − mice with a TCRβ 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. leukemia development hematopoiesis lymphocyte stem cells Footnotes Submitted: 5 February 2001 Revision requested 1 May 2001 Accepted: 24 May 2001

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Jul 2, 2001

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