Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia

Cyclic neutropenia (CN) is a congenital hematopoietic disorder characterize d by remarkably regular oscillations of blood neutrophils from near normal to extremely low levels at 21-day intervals, Recurring episodes of severe n eutropenia lead to repetitive and sometimes life-threatening infections. To investigate the cellular mechanism of CN, the ultrastructure and the proli ferative and survival characteristics of bone marrow-derived CD34(+) early progenitors, CD33(+)/CD34(-) myeloid progenitors, and CD15(+) neutrophil pr ecursors from CN patients and healthy volunteers were studied, The ultrastr uctural studies showed profound apoptotic features in bone marrow progenito r cells in CN, Colony-forming assays demonstrated a 75% decrease in the num ber of early myeloid-committed colonies compared with controls. Long-term c ulture-initiating cell assays demonstrated a 6-fold increase in production of primitive progenitor cells in CN, To determine whether accelerated apopt osis might account for the underproduction of myeloid progenitors, the hema topoietic subpopulations were labeled with fluorescein isothiocyanate-annex in V and analyzed by flow cytometry. Short-term culture of CN cells resulte d in apoptosis of approximately 65% of CD34(+) cells, 80% of CD33(+)/CD34(- ) cells, and more than 70% of CD15(+) cells, as compared with 20%, 7%, and 15% apoptosis in respective control subpopulations, Evidence of accelerated apoptosis of bone marrow progenitor cells was observed in all 8 patients p articipating in the study, regardless of the stage in the CN cycle in which bone marrow aspirations were obtained, Granulocyte colony-stimulating fact or therapy of CN patients significantly improved survival of bone marrow pr ogenitor cells. These data indicate that ineffective production of neutroph ils is due to accelerated apoptosis of bone marrow myeloid progenitor cells in CN. (C) 2001 by The American Society of Hematology.