Abstract
The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) regulates major apoptotic and growth-suppressive pathways. In APL, PML is involved in a chromosomal translocation generating the PML-retinoic acid receptor-alpha (RARalpha) fusion protein. Two missense mutations in the remaining PML alleles have been identified, which give rise to a truncated cytoplasmic PML protein (Mut PML). APL patients carrying these mutations display resistance to retinoic acid (RA) and very poor prognosis. Here we show that Mut PML associates with the cytoplasmic regions we refer to as PML-cytoplasmic bodies (PML-CBs). Mut PML interacts with PML-RARalpha in PML-CB and potentiates PML-RARalpha-mediated inhibition of RA-dependent transcription. Remarkably, Mut PML stabilizes PML-RARalpha and inhibits differentiation induced by pharmacological doses of RA. A mutant form of PML-RARalpha that accumulates in the cytoplasm inhibits RA-dependent transcription and differentiation, thus suggesting that cytoplasmic localization of PML-RARalpha may contribute to transformation. Finally, we show that the bcr3 PML-RARalpha form is predominantly cytoplasmic and accumulates in PML-CBs. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.
Highlights
The promyelocytic leukemia (Pml) gene encodes a tumor suppressor involved in the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL),2 and which produces the fusion protein PML-RAR␣ [1]
As a recent study indicated that cytoplasmic PML isoforms are associated with early endosomes [13], we attempted to verify whether Mut PML 1 (Mut PML) colocalizes with the early endosomal marker EEA1 but failed to reveal a colocalization with these organelles (Fig. 1C)
The PML-nuclear body (PML-NB) components Daxx and Sp100 did not associate with PML cytoplasmic bodies (PML-CB) upon coexpression of Mut PML in fibroblasts and hematopoietic cells
Summary
The promyelocytic leukemia (Pml) gene encodes a tumor suppressor involved in the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL), and which produces the fusion protein PML-RAR␣ [1]. PML-RAR␣ is able to act as a dominant-negative retinoic acid receptor, inhibiting the response to RA and blocking RAinduced differentiation [4]. This function is mainly exerted through changes at the chromatin level through the recruitment of histone deacetylases and methyltransferases [5,6,7]. A recent study conducted on a cohort of 17 RAresistant APL cases identified two Pml mismatch mutations in the remaining allele, which are associated with very aggressive disease [14] Both mutations (1272delAG and IVS3–1G-A) generate a premature stop codon upstream of the nuclear localization signal. We found that a PML-RAR␣ mutant that accumulates in the cytoplasm retains the ability to inhibit RA-dependent transcription and differentiation
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