Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 118, Issue 9, Pages 3181-3194Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI35090
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Funding
- University of Pennsylvania Center for Clinical Epidemiology and Biostatistics
- University Laboratory Animal Resource (ULAR)
- NIH
- Leukemia and Lymphoma Society SCORE Program
- National Cancer Institute [5K08 CA 120544-02]
- NIH/NIDDK [T32-DK007780-07]
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Gain-of-function NOTCH1 mutations are found in 50%-70% of human T cell acute lymphoblastic leukemia/ lymphoma (T-ALL) cases. Gain-of-function NOTCH1 alleles that initiate strong downstream signals induce leukemia in mice, but it is unknown whether the gain-of-function NOTCH1 mutations most commonly found in individuals with T-ALL generate downstream signals of sufficient strength to induce leukemia. We addressed this question by expressing human gain-of-function NOTCH1 alleles of varying strength in mouse hematopoietic precursors. Uncommon gain-of-function NOTCH1 alleles that initiated strong downstream signals drove ectopic T cell development and induced leukemia efficiently. In contrast, although gain-of-function alleles that initiated only weak downstream signals also induced ectopic T cell development, these more common alleles failed to efficiently initiate leukemia development. However, weak gain-of-function NOTCH1 alleles accelerated the onset of leukemia initiated by constitutively active K-ras and gave rise to tumors that were sensitive to Notch signaling pathway inhibition. These data show that induction of leukemia requires doses of Notch I greater than those needed for T cell development and that most NOTCH1 mutations found in T-ALL cells do not generate signals of sufficient strength to initiate leukemia development. Furthermore, low, nonleukemogenic levels of Notch1 can complement other leukemogenic events, such as activation of K-ras. Even when Notch 1 participates secondarily, the resulting tumors show addiction to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia.
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