Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies

Abstract

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA-or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoidtreated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.

Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells

“…15,30,31 The results obtained here with NPM1 mutant AML unexpectedly bear some similarities with APL. First, mutant NPM1 is degraded with RA or arsenic exposure, and p53 signaling is activated.…”

TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia

“…In our present study, TBLR1-RARa could increase the sensitivity of U937 and HL-60 cells to ATRA and induce a dose-and time-dependent cell differentiation, which was consistent with previous luciferase assays. Besides mediating the degradation of corepressors, TBLR1-RARa was found to be degraded as PML-RARa 47 and homodimerization of TBLR1-RARa were interfered with in the presence of ATRA, which was also responsible for transactivation and cell differentiation.…”

p53 as an Effector or Inhibitor of Therapy Response

“…This actually explained why RA and arsenic antagonize each other for differentiation (Shao et al 1998), but sharply synergize for APL eradication in vivo (Lallemand-Breitenbach et al 1999;Rego et al 2000). The second essential step was the realization that differentiation is linked to transcriptional activation (or derepression), although loss of self-renewal is the direct consequence of PML/RARA loss Ablain et al 2013). Subsequent studies indeed revealed that therapy-induced PML/RARA degradation triggers a p53 response.…”

“…these two otherwise unrelated agents. Studies performed in mouse models of APL have conclusively shown that PML/RARA loss is responsible for the abrogation of APL self-renewal Ablain et al 2013Ablain et al , 2014. Subsequent studies showed that PML/RARA loss is actually sufficient for differentiation, thus explaining in vivo myeloid maturation on arsenic exposure (Vitaliano-Prunier et al 2014).…”