Ex vivo interaction of bone marrow stromal cells with Ring1B-expressing and -non expressing immortalized HSPC

Polycomb group (PcG) of genes is involved in the maintenance of cell identities from early embryo to adult tissue homeostasis, mostly through gene expression silencing. There are two distinct groups of PcG proteins that assemble into two major types of multiheteromeric complexes, namely Polycomb Repressing Complex 1 and 2 (PRC1 and PRC2). Both are endowed with histone-modifying activities, being PRC1 responsible for H2A ubiquitylation through their core enzyme Ring1B or its paralog Ring1A. Although structurally and biochemically similar, Ring1B seems to have unique functions not fulfilled by Ring1A. Ring1B has been involved in hematopoietic homeostasis, with distinct roles in different bone marrow cell compartments during physiological hematopoiesis. Thus, Ring1B appears to assure proliferation in mature populations, but restrains the expansion of the most immature, multipotent and oligopotent progenitors. Accordingly, we have shown a decrease in mature lymphoid and myeloid cells when ablated in the adult mice, together with an increased proliferation of myeloid progenitors (1). It has also been reported that Ring1B is essential for Mll-Af9 myeloid transformation and survival of leukemic cells, and proposed as a pro-oncogenic factor (2). However, when deleted in vivo in the absence of Ink4, Ring1B KO reduces the time of Ink4KO-driven hematological malignancies onset, thus acting in this context as an anti-oncogenic factor (1). We have been able to immortalize Ring1B deficient early progenitors with different oncogenic challenges. It is possible that Ring1B may intervene in distinct cell proliferation mechanisms, depending on the cell compartment and/or level of lineage differentiation. We have also asked whether primary as well as immortalized progenitors may be differently affecting bone marrow stromal cells depending on the level of maturation and of Ring1B expression. We will also present data obtained from ex vivo experiments performed to elicit the possible role of Ring1B on the interaction between hematopoietic cells and the cellular microenvironment. (1) Calés et al MCB (2008) 28, 1018-1028. (2) Van den Boom et al (2016) Cell Reports 14, 332-346.