Signal transduction in MDS bone marrow populations DISTINCT SIGNAL TRANSDUCTION ABNORMALITIES AND ERYTHROPOIETIN RESPONSE IN BONE MARROW HEMATOPOIETIC CELL SUBPOPULATIONS OF MYELODYSPLASTIC SYNDROME PATIENTS

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS. Experimental design: Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of ERK1/2, p38 MAPK, and STAT5 specifically in defined CD34+, CD45+, or CD71+CD45bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with G-CSF and erythropoietin (EPO). Results: In CD71+CD45cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous EPO levels, transfusion dependency, percentage of blasts in the BM), EPO failed to activate ERK1/2 or STAT5 in 23/36 cases, but it was effective in 13/36 cases, although to a significantly lower degree than in CD71+CD45cells from healthy donor BM. The EPO response in vivo correlated with in vitro EPO-dependent STAT5 activation in 20/22 cases. STAT5 was significantly activated at baseline in MDS cells compared to normal controls, while caspase-3 was activated in CD34+ and CD45+ MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34+ cells. Conclusions: Abnormalities in the response to growth factors are restricted to EPO stimulation in CD71+CD45cells and correlate with the clinical response to EPO. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS, but with different patterns among the various BM subpopulations. Research. on July 16, 2017. © 2012 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on April 11, 2012; DOI: 10.1158/1078-0432.CCR-11-0686