NPM1-ALK-dependent repression of pRB phosphorylation

Stable Identifier
R-HSA-9851127
Type
Reaction [uncertain]
Species
Homo sapiens
Compartment
nucleoplasm, cytosol
ReviewStatus
5/5
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NPM1-ALK-dependent repression of pRB phosphorylation
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Before NPM1-ALK-containing ALCL cells progress to unrestrained proliferative growth and transformation, they appear to be subject to an early phase of NPM1-ALK-induced senescence that depends on cell cycle arrest rather than cell death (Martinelli et al, 2011; McDuff et al, 2011). Independent studies have identified CDKN2A (p16INK4a) and/or TP53/RB1 as mediators of this pre-transformation arrest in NPM1-ALK cell lines and mouse models. Cells are characterized by low proliferation rates, low incorporation of BrDU, expression of senescence-associated beta galactosidase and accumulation of hypophosphorylated RB1 protein (the form that promotes cell cycle arrest) (Martinelli et al, 2011; McDuff et al, 2011). The Martinelli study identified CDKN2A/p16INK4a as a critical effector of NPM1-ALK mediated cell cycle arrest as the block on proliferation was abolished in a CDKN2A/p16INK4a negative background and tumor development in CDKN2A/p16INK4a- transgenic mice was accelerated. Consistent with this, CDKN2A/p16INK4a expression is upregulated in an NPM1-ALK-, STAT3- and JMJD3- (a H3K27 histone demethylase) dependent manner in MEFs expressing NPM1-ALK (Martinelli et al, 2011). In contrast, although CDKN2A/p16INK4a was implicated in cell cycle arrest in the McDuff study, deletion of this locus was not sufficient to relieve the block on proliferation in NPM1-ALK cells. Instead, the cell cycle arrest was shown to depend on the TP53 and RB1 pathways - paradoxically in the absence of TP53 stabilization or CDKN1A/p21 induction (McDuff et al, 2011).
Literature References
PubMed ID Title Journal Year
21423761 Aberrant anaplastic lymphoma kinase activity induces a p53 and Rb-dependent senescence-like arrest in the absence of detectable p53 stabilization

McDuff, FK, Turner, SD

PLoS One 2011
21518927 The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway

Chiarle, R, Bonetti, P, Inghirami, G, McDuff, FK, Colombo, E, Raviele, PR, Fumagalli, C, Martinelli, P, Pileri, S, Pruneri, G, Turner, SD, Sironi, C, Tusi, BK, Volorio, S, Pelicci, PG

Blood 2011
Participants
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Output
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as an event of
This event is regulated
Negatively by
Regulator
NPM1(1-117)-p-7Y ALK(1058-1620) fusion dimer [nucleoplasm] (Homo sapiens)
Disease
Name Identifier Synonyms
anaplastic large cell lymphoma DOID:0050744
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2023-10-14)
Reviewed
Turner, S  (2023-11-08)
Created
Rothfels, K  (2023-10-12)
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