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 CD3 epsilon and pre-T alpha mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2(-/)- mice with a TCR beta 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.
Allman
D
D
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Karnell
F G
FG
Punt
J A
JA
Bakkour
S
S
Xu
L
L
Myung
P
P
Koretzky
G A
GA
Pui
J C
JC
Aster
J C
JC
Pear
W S
WS
D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C499308:Rag2 protein, mouse; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2