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Details on Person Before NPM1-ALK-containing ALCL cells progress to unrestrain...
| Class:Id | Summation:9850830 |
|---|---|
| _displayName | Before NPM1-ALK-containing ALCL cells progress to unrestrain... |
| _timestamp | 2023-10-12 18:30:03 |
| created | [InstanceEdit:9850804] Rothfels, Karen, 2023-10-12 |
| text | 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). |
| (summation) | [BlackBoxEvent:9851127] NPM1-ALK-dependent repression of pRB phosphorylation [Homo sapiens] |
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