A Pin1/PML/P53 axis activated by retinoic acid in <i>NPM-1c</i> acute myeloid leukemia

Abstract

Retinoic acid (RA) was proposed to increase survival of chemotherapy-treated Nucleophosmin-1 mutated Acute Myeloid Leukemia patients (NPM-1c AMLs). We reported that ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blasts response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in NPM-1c AML patients.

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

“…In that sense, the addition of retinoic acid and arsenic trioxide synergistically mediated the proteasomal degradation of NPM1c in AML cell lines and in primary blasts from NPM1c AML patients, leading to differentiation and apoptosis [ 25 , 26 ]. More importantly, retinoic acid and arsenic treatment significantly reduced blasts in some NPM1c AML patients who were unfit to chemotherapy [ 25 , 38 ]. Likewise, Actinomycin D induced complete remissions in NPM1c AMLs [ 28 , 48 , 49 ], and this clinical efficacy happened via targeting mitochondria, boosting reactive oxygen species production, hence restoring senescence of NPM1c expressing cells.…”

“…Beads were washed 3 times in the IP buffer prior to elution of immuno-precipitated proteins in sample buffer. Cell extracts were separated on 4% to 12% gradient gels (Invitrogen, Waltham, MA, USA) as described [ 38 ].…”

“…Moreover, the post-translational modifications of NPM1 affect the therapeutic response in AML, whereby SENP3-mediated deSUMOylation of NPM1 induced the resistance of AML cells to chemo- and radiotherapy [ 36 ]. We and others demonstrated that drugs targeting NPM1c induce a selective growth arrest and apoptosis in NPM1c AML cells [ 25 , 26 , 37 , 38 , 39 ]. Particularly, we demonstrated that the imidazoquinoxaline EAPB0503, an Imiquimod analog, induced the selective growth arrest and apoptosis in NPM1c AML cell lines and in ex vivo treated blasts from NPM1c AML patients.…”

Pancreatic Tumor Eradication via Selective PIN1 Inhibition in Cancer Associated Fibroblasts and T Lymphocytes Engagement

“…Besides, a few available drugs have been repurposed for PIN1 inhibition in tumors, which can generally inhibit PIN1 but can't restrict the inhibition within specific cell population of the tumor 17,[20][21][22][23][24] . The DNA-barcoded micellular systems we are developing in this work prove the feasibility to regulate PIN1 in cell population of interest.…”

“…Pharmacological inhibition of PIN1 has therefore been regarded as a potent anticancer strategy 17 . A few small molecule compounds that inhibit PIN1, such as all-trans retinoic acid, arsenic trioxide, juglone, AG17724, KPT-6566 and sulfopin, have been identified and used or repurposed for investigating roles of PIN1 in oncogenesis [20][21][22][23][24] . All these compounds, when applied in vivo, even though a small fraction of injected amount can finally distribute into tumor and affect tumor progression via inhibiting PIN1 there, it is unclear how much different cell population, like CAFs, of the tumor contributes.…”