Person:

Mendez, Lourdes

Disease recurrence after therapy, due to the persistence of resistant leukemic cells, represents a fundamental problem in the treatment of leukemia. Elucidating the mechanisms responsible for the maintenance of leukemic cells, before and after treatment, is therefore critical to identify curative modalities. It has become increasingly clear that cell-autonomous mechanisms are not solely responsible for leukemia maintenance. Here, we report a role for Pml in mesenchymal stem cells (MSCs) in supporting leukemic cells of both CML and AML. Mechanistically, we show that Pml regulates pro-inflammatory cytokines within MSCs, and that this function is critical in sustaining CML-KLS and AML ckit+ leukemic cells non-cell autonomously.

The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.