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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2669-2677.
Prepublished online as a Blood First Edition Paper on June 20, 2006; DOI 10.1182/blood-2006-02-005900.
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IMMUNOBIOLOGY
c-Myc mediates pre-TCR-induced proliferation but not developmental progression
Marei Dose,
Irum Khan,
Zhuyan Guo,
Damian Kovalovsky,
Andreas Krueger,
Harald von Boehmer,
Khashayarsha Khazaie, and
Fotini Gounari
From the Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA; the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown.
Constitutive and cell-autonomous signals emanating from the pre-T-cell receptor (pre-TCR) promote proliferation, survival and differentiation of immature thymocytes. We show here that induction of pre-TCR signaling resulted in rapid elevation of c-Myc protein levels. Cre-mediated thymocyte-specific ablation of c-Myc in CD25+CD44- thymocytes reduced proliferation and cell growth at the pre-TCR checkpoint, resulting in thymic hypocellularity and a severe reduction in CD4+CD8+ thymocytes. In contrast, c-Myc deficiency did not inhibit pre-TCR-mediated differentiation or survival. Myc-/- double-negative (DN) 3 cells progressed to the double-positive (DP) stage and up-regulated TCR  surface expression in the absence of cell proliferation, in vivo as well as in vitro. These observations indicate that distinct signals downstream of the pre-TCR are responsible for proliferation versus differentiation, and demonstrate that c-Myc is only required for pre-TCR-induced proliferation but is dispensable for developmental progression from the DN to the DP stage.
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