In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications

He, Lizhen; Merghoub, Taha; Pandolfi, Pier Paolo

doi:10.1038/sj.onc.1203088

Cited by 93 publications

(94 citation statements)

References 113 publications

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“…This fusion protein is present in the APL cell line NB4 (He et al, 1999). Staining NB4 cells with anti-PML exposed PML protein predominantly in nuclear microspeckles ( Figure 2) that, as earlier studies have shown, co-localize with the RXR transcription factor (Dyck et al, 1994;Koken et al, 1994;Weis et al, 1994).…”

Section: Blm Is Delocalized From the Nb In The Presence Of Pml-rarasupporting

confidence: 69%

“…The PML gene was identi®ed at the translocation breakpoint in APL cells that contain the chromosomal translocation t(15;17) (for reviews see Melnick and Licht, 1999;He et al, 1999). Gene-targeted disruption of PML demonstrates that the PML protein functions as a growth and tumor suppressor in vivo, and it is important for multiple apoptotic pathways (Wang et al, 1998a,b).…”

Section: Introductionmentioning

confidence: 99%

“…In APL cells harboring the t(15;17), the PML gene is fused to RARa leading to the generation of a PMLRARa fusion protein (Pandol® et al, 1991;de The et al, 1991;Kakizuka et al, 1991;Goddard et al, 1991;He et al, 1999). The PML-RARa fusion protein is leukemogenic in transgenic mice (He et al, 1997(He et al, , 1998Grisolano et al, 1997;Brown et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The PML-RARa fusion protein is leukemogenic in transgenic mice (He et al, 1997(He et al, , 1998Grisolano et al, 1997;Brown et al, 1997). PML-RARa retains most of the functional domains of its parental proteins and can heterodimerize with PML (He et al, 1999). In APL cells, PML no longer localizes to the NB but instead forms nuclear microspeckles that are coincident with PML-RARa and RXR (Dyck et al, 1994;Koken et al, 1994;Weis et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, it is tempting to speculate that PML-RARa interferes with their normal functions as well. Treatment of persons with APL with RA can achieve complete but temporary clinical remission of this disease, and in APL cells, it causes the degradation of PML-RARa and induces relocalization of NB components (He et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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A role for PML and the nuclear body in genomic stability

et al. 1999

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The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are disrupted in APL cells. The Bloom syndrome gene BLM encodes a RecQ DNA helicase, whose absence from the cell results in genomic instability epitomized by high levels of sister-chromatid exchange (SCE) and cancer predisposition. We show here that BLM colocalizes with PML to the NB. In cells from persons with Bloom syndrome the localization of PML is unperturbed, whereas in APL cells carrying the PML-RARa oncoprotein, both PML and BLM are delocalized from the NB into microspeckled nuclear regions. Treatment with retinoic acid (RA) induces the relocalization of both proteins to the NB. In primary PML7/7 cells, BLM fails to accumulate in the NB. Strikingly, in PML7/7 cells the frequency of SCEs is increased relative to PML+/+ cells. These data demonstrate that BLM is a constituent of the NB and that PML is required for its accumulation in these nuclear domains and for the normal function of BLM. Thus, our ®ndings suggest a role for BLM in APL pathogenesis and implicate the PML NB in the maintenance of genomic stability.

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Section: Blm Is Delocalized From the Nb In The Presence Of Pml-rarasupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A role for PML and the nuclear body in genomic stability

et al. 1999

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The puzzling multiple lives of PML and its role in the genesis of cancer

2000

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PML, the gene associated with acute promyelocytic leukemia (APL); PML, the target of numerous viral agents; PML, the growth suppressor; PML, the mediator of multiple apoptotic pathways; PML, the tumor suppressor; PML, the protein which epitomizes a novel nuclear structure, the nuclear body; PML, the transcription co-factor. Despite the recent flurry of reports attributing multiple biological roles to the PML protein, PML still lacks a definitive biochemical function. This is probably the reason why PML is so attractive to many investigators. Here, we will summarize the facts and speculations on this puzzling protein.

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