Favorable and poor prognosis B-cell precursor acute lymphoblastic leukemia subtypes reveal distinct leukemic cell properties when interacting with mesenchymal stem cells, differentially modifying their cell stemness and leukemia chemoresistance

The development of B-ALL alters the bone marrow microenvironment influencing disease progression and response to therapy. The aggressiveness of particular B-ALL subtypes could be related to specific mechanisms used to reprogram bone marrow stromal cells. The purpose of this study is to compare the effect of two B-ALL subtypes, with opposite prognosis, on mesenchymal stem cells (MSC) functions and the consequences on leukemic cell properties. We have established an in vitro leukemic niche (LN) by co-culturing MSC with REH (favorable prognosis) or SUP-B15 (poor prognosis) B-ALL cell lines and examined leukemic-induced MSC reprogramming and its impact on leukemic cells properties and drug resistance. The aggressive SUP-B15 cell line showed faster and stronger adherence to MSC and increased migration to CXCL12 and LN secretome, compared to REH cells. SUP-B15 cell proliferation was reduced but modulated over time. No differences in MSC senescence induction or recovery were observed between both cell lines. Interestingly, the SUP-B15 LN secretome was enriched in IL-6, IL-8, CCL2 and MIF. MSC pre-incubated with CCL2 showed increased MSC senescence but this did not alter protection against cytotoxic drugs. On the contrary, MSC self-renewal and adipogenic differentiation were also increased in the aggressive SUP-B15 cell line, strengthening protection against the cytotoxic drugs vincristine, methotrexate and doxorubicin. This study showed that the aggressiveness of certain leukemia subtypes is also associated with specific changes induced in MSC secretome and stemness that have an impact on specific properties of leukemic cells, improving LN fitness and ability to survive to cytotoxic drugs.