Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/115972
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Type: Journal article
Title: Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential
Author: Treanor, L.M.
Zhou, S.
Janke, L.
Churchman, M.L.
Ma, Z.
Lu, T.
Chen, S.-C.
Mullighan, C.G.
Sorrentino, B.P.
Citation: Journal of Experimental Medicine, 2014; 211(4):701-713
Publisher: Rockefeller University Press
Issue Date: 2014
ISSN: 0022-1007
1540-9538
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Responsibility: 
Louise M. Treanor, Sheng Zhou, Laura Janke, Michelle L. Churchman, Zhijun Ma, Taihe Lu, Shann-Ching Chen, Charles G. Mullighan, Brian P. Sorrentino
Abstract: Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) exhibits lymphoid, myeloid, and stem cell features and is associated with a poor prognosis. Whole genome sequencing of human ETP-ALL cases has identified recurrent mutations in signaling, histone modification, and hematopoietic development genes but it remains to be determined which of these abnormalities are sufficient to initiate leukemia. We show that activating mutations in the interleukin-7 receptor identified in human pediatric ETP-ALL cases are sufficient to generate ETP-ALL in mice transplanted with primitive transduced thymocytes from p19(Arf-/-) mice. The cellular mechanism by which these mutant receptors induce ETP-ALL is the block of thymocyte differentiation at the double negative 2 stage at which myeloid lineage and T lymphocyte developmental potential coexist. Analyses of samples from pediatric ETP-ALL cases and our murine ETP-ALL model show uniformly high levels of LMO2 expression, very low to undetectable levels of BCL11B expression, and a relative lack of activating NOTCH1 mutations. We report that pharmacological blockade of Jak-Stat signaling with ruxolitinib has significant antileukemic activity in this ETP-ALL model. This new murine model recapitulates several important cellular and molecular features of ETP-ALL and should be useful to further define novel therapeutic approaches for this aggressive leukemia.
Keywords: p38 Mitogen-Activated Protein Kinases
Rights: © 2014 Treanor et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
DOI: 10.1084/jem.20122727
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