Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse

Sportoletti, Paolo; Grisendi, Silvia; Majid, Samia; Cheng, Ke; Clohessy, John G.; Viale, Agnès; Teruya‐Feldstein, Julie; Pandolfi, Pier Paolo

doi:10.1182/blood-2007-06-098251

Cited by 116 publications

(98 citation statements)

References 9 publications

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“…46 Npm1 ϩ/Ϫ mice show higher susceptibility for development of malignancies, especially of hematological and lymphoid origin, than their wild-type counterparts, indicating NPM as a haploinsufficient tumor suppressor. 29 Here we show that reduced NPM protein expression was associated with poor prognosis and that over-expression of NPM in the MDA-MB-231 breast cancer cells abrogated their growth in soft agar, supporting a tumor suppressive function for NPM in breast cancer. Previously, high NPM expression has been associated with poor prognosis or recurrence in Ewing's sarcoma, 48 hepatocellular carcinoma, 34 bladder cancer, 49 prostate cancer, 28 colon carcinoma, 50 and gastric carcinoma.…”

Section: Discussionsupporting

confidence: 51%

“…function is required for the maintenance of genomic stability, [27][28][29] and NPM1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment. 29 To shed light on the role of NPM in solid cancers, we investigated NPM expression levels and localization in a large array of human breast carcinoma samples (n ϭ 1160) and evaluated its association with clinicopathological variables, patient survival, and molecular subtypes of breast cancer.…”

Section: Npm1mentioning

confidence: 99%

“…29 To shed light on the role of NPM in solid cancers, we investigated NPM expression levels and localization in a large array of human breast carcinoma samples (n ϭ 1160) and evaluated its association with clinicopathological variables, patient survival, and molecular subtypes of breast cancer. We identified granular staining as a novel staining pattern for NPM.…”

Section: Npm1mentioning

confidence: 99%

See 2 more Smart Citations

An Extensive Tumor Array Analysis Supports Tumor Suppressive Role for Nucleophosmin in Breast Cancer

Karhemo

Rivinoja

Lundin

et al. 2011

The American Journal of Pathology

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Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its expression and localization in histologically normal breast tissue and a large array of human breast carcinoma samples (n ‫؍‬ 1160), and also evaluated its association with clinicopathological variables and patient survival. The intensity and localization (nucleolar, nuclear, cytoplasmic) of NPM varied across clinical samples. No mutations explaining the differences were found, but the present findings indicate that expression levels of NPM affected its localization. Our study also revealed a novel granular staining pattern for NPM, which was an independent prognostic factor of poor prognosis. In addition, reduced levels of NPM protein were associated with poor prognosis. Nucleophosmin (NPM) is a ubiquitously expressed multifunctional nucleolar phosphoprotein. It localizes mainly to the nucleoli, but also shuttles in and out of the nucleolus, and between the nucleus and the cytoplasm. 1,2 NPM belongs to the nucleoplasmin family of nuclear chaperone proteins. It is involved in a complex network of interactions and has multiple functions. In addition to its chaperone activity, 3,4 NPM is involved in centrosome duplication, 5 ribosome biogenesis, 6,7 and environmental stress responses. 8,9 NPM also regulates the tumor suppressor proteins p53 10 -12 and p14 ARF . [13][14][15] Moreover, NPM protein is post-translationally modified by acetylation, 16 sumoylation, 17,18 ubiquitinylation, 19 and phosphorylation. 20 -23 NPM has been heavily implicated in cancer pathogenesis, but its actual role in oncogenesis is controversial. 24 NPM1 is mutated or rearranged in a number of hematological disorders, 25 and it is the most frequently mutated gene in acute myeloid leukemia. In addition, NPM protein is reported to be overexpressed in cancer cells, and it was originally proposed as a proto-oncogene. However, rapidly proliferating tumor cells could show elevated NPM levels, simply because NPM expression increases rapidly in early G1 phase during mitosis. 26 On the other hand, inactivation of NPM1 in the germline leads to embryonic lethality. 27,28 Moreover, experiments with cultured NPM-null cells 27,28 and mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. 27 NPM1

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Section: Discussionsupporting

confidence: 51%

Section: Npm1mentioning

confidence: 99%

Section: Npm1mentioning

confidence: 99%

See 1 more Smart Citation

An Extensive Tumor Array Analysis Supports Tumor Suppressive Role for Nucleophosmin in Breast Cancer

Karhemo

Rivinoja

Lundin

et al. 2011

The American Journal of Pathology

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show abstract

“…On the other hand, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM (Feuerstein et al, 1988). Moreover, tumor suppressive role for NPM is reported in breast cancer (Karhemo et al, 2011) and NPM acts as a haploinsufficient tumor suppressor in the hematopoietic compartment (Sportoletti et al, 2008). NPM functions both as oncogene and tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Role of Nucleophosmin in Colorectal Carcinomas

Yang¹,

Zhang²,

Yang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Like APC, the gene encoding NPM1 lies outside the conventional (del)5 or 5q-CDRs. Mice heterozygous for NPM1 develop many features similar to human MDS (Sportoletti et al, 2008); 75% of such mice develop myeloid malignancies, whereas others develop B-and T-cell malignancies. The peripheral blood shows elevated levels of white blood cells and leukemic blasts, myeloid expansion and proliferation, and anemia and thrombocytopenia.…”

Section: Npm1-targeted Micementioning

confidence: 99%

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

et al. 2009

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Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse

Cited by 116 publications

References 9 publications

An Extensive Tumor Array Analysis Supports Tumor Suppressive Role for Nucleophosmin in Breast Cancer

An Extensive Tumor Array Analysis Supports Tumor Suppressive Role for Nucleophosmin in Breast Cancer

Prognostic Role of Nucleophosmin in Colorectal Carcinomas

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

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