Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse.
Nucleophosmin (NPM1) gene has been heavily implicated in cancer pathogenesis both as a putative proto-oncogene and tumor suppressor gene. NPM1 is the most frequently mutated gene in acute myeloid leukemia (AML), while deletion of 5q, where NPM1 maps, is frequent in patients with myelodysplastic syndromes (MDS). We have previously shown that mice heterozygous for Npm1 (Npm1+/-) develop a hematologic syndrome with features of human MDS. Here we analyzed Npm1+/- mutants to determine their susceptibility to cancer. Npm1+/- mice displayed a greater propensity to develop malignancies compared with Npm1+/+ mice. The Npm1+/- cohort frequently developed hematologic malignancies of both myeloid and lymphoid origin with myeloid malignancies displaying the highest incidence. Malignant cells retained the wild-type allele with normal localization and expression of Npm1 at the protein level, suggesting that complete Npm1 loss is not a prerequisite for tumorigenesis. Our results conclusively demonstrate that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment.
Sportoletti
Paolo
P
Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Grisendi
Silvia
S
Majid
Samia M
SM
Cheng
Ke
K
Clohessy
John G
JG
Viale
Agnes
A
Teruya-Feldstein
Julie
J
Pandolfi
Pier Paolo
PP
D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin