Abstract
The consequences of immune dysfunction in B-chronic lymphocytic leukemia (CLL) likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients. The well-described immune abnormalities are not able to consistently explain these complications. Here, we report bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. Numbers of CD34+ BM hematopoietic progenitors responsive in standard colony-forming unit (CFU) assays, including CFU-GM/GEMM and CFU-E, were significantly reduced. Flow cytometry revealed corresponding reductions in frequencies of all hematopoietic stem and progenitor cell (HSPC) subsets assessed in CLL patient marrow. Consistent with the reduction in HSPCs, BM resident monocytes and natural killer cells were reduced, a deficiency recapitulated in blood. Finally, we report increases in protein levels of the transcriptional regulators HIF-1α, GATA-1, 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 TNFα, a cytokine constitutively produced by CLL B cells. Together, these findings reveal BM hematopoietic dysfunction in untreated CLL patients that provides new insight into the etiology of the complex immunodeficiency state in CLL.
Key points
Cell-intrinsic defects in BM hematopoietic stem and progenitor cells (HSPCs) in untreated CLL patients.
Altered levels of specific nuclear factors regulating HSPC differentiation and function in untreated CLL patients.
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Acknowledgments
This work was supported by funding provided by the Mayo Clinic Center for Biomedical Discovery to K.L.M., W.D., and N.E.K. B.A.M. is supported by a NIH T32 Training Grant in Basic Immunology (NIH AI07425).
Author contributions
B.A.M., H.Z., N.E.K., and K.L.M. designed experiments; B.A.M., H.Z., M.M., K.A.G., and C.R.S. performed and analyzed experiments; B.A.M., N.E.K., and K.L.M. wrote the manuscript.
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Research funding has been provided to the institution from Pharmacyclics, Morphosys, and AbbVie for clinical studies in which Dr. Sameer Parikh is a principal investigator. Dr. Sameer Parikh has also participated in Advisory Board meetings of Pharmacyclics, AstraZeneca, and AbbVie (he was not personally compensated for his participation).
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Manso, B.A., Zhang, H., Mikkelson, M.G. et al. Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients. Leukemia 33, 638–652 (2019). https://doi.org/10.1038/s41375-018-0280-0
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DOI: https://doi.org/10.1038/s41375-018-0280-0
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