Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia.
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.
Chiang
Mark Y
MY
Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Xu
Lanwei
L
Shestova
Olga
O
Histen
Gavin
G
L'heureux
Sarah
S
Romany
Candice
C
Childs
M Eden
ME
Gimotty
Phyllis A
PA
Aster
Jon C
JC
Pear
Warren S
WS
D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1