Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia

• Published in: The Journal of clinical investigation 2008-09, Vol.118 (9), p.3181-3194
• Main Authors: Chiang, Mark Y, Xu, Lanwei, Shestova, Olga, Histen, Gavin, L'heureux, Sarah, Romany, Candice, Childs, M Eden, Gimotty, Phyllis A, Aster, Jon C, Pear, Warren S
• Format: Article
• Language: English
• Subjects: Alleles; Allelomorphism; Animals; Biomedical research; Cell Line, Tumor; Complications and side effects; Gene Expression Regulation, Leukemic; Gene mutations; Genes, ras; Genetic aspects; Health aspects; Humans; Leukemia; Ligands; Lymphocytes; Lymphocytic leukemia; Lymphoma; Mice; Mice, Inbred C57BL; Models, Biological; Models, Genetic; Mutation; Physiological aspects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Receptor, Notch1 - genetics; Receptor, Notch1 - physiology; Signal Transduction; Time Factors; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI35090

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 Notch1 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 Notch1 participates secondarily, the resulting tumors show "addiction" to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia.