The Experimental Study Of Bone Marrow Hematopoietic Dysfunction In Chronic Lymphocytic Leukemia

Immune dysfunction is a cardinal feature of chronic lymphocytic leukemia(CLL)from its early stage and worsens during clinical observation,even in absence of disease progression.The known immune abnormalities are not able to consistently explain these complications and it is not easy to correct their immune status.The consequences of immune dysfunction in CLL likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients.Here,we report bone marrow(BM)hematopoietic dysfunction in early and late stage untreated CLL patients.We found reduced functional capacity of hematopoietic progenitors in BM using colony forming unit assays and flow cytometry revealed significant reductions in frequencies of hematopoietic stem cells(HSC),multipotent progenitors(MPP),common myeloid progenitors(CMP),and myelo-erythroid progenitors(MEP).Consistent with the reduction in hematopoietic stem and progenitor cells(HSPC),monocytes and natural killer cells in BM were reduced and the reduction in BM was recapitulated in blood.Finally,we report imbalances in protein levels of the transcriptional regulators hypoxia-inducible factor 1-alpha(HIF-1α),PU.1,and GATA-2 in CLL patient BM,providing molecular insight into the basis of HSPC dysfunction.Importantly,PU.1 and GATA-2 were rapidly increased when healthy HSPCs were exposed in vitro to tumor necrosis factor-α(TNFα),a cytokine constitutively produced by CLL B cells.Together,these findings reveal BM hematopoietic dysfunction in untreated CLL patients,adding to the complex immunodeficiency state of these patients and the reduced capacity of the innate immune system.