BCR/ABL(-) CD34(+)HLA-DR- progenitor cells in early chronic phase, but notin more advanced phases, of chronic myelogenous leukemia are polyclonal

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph ) translocation and BCR/ABL gene rearrangement which occur in a pluripotent hematopoietic progenitor cell. Ph-negative (Ph-) hematopoiesis can be rest ored in vivo after treatment with a-interferon or intensive chemotherapy, s uggesting that normal stem and progenitor cells coexist with the Ph+ clone, We have previously shown that Ph- progenitors are highly enriched in the C D34(+)HLA-DR- fraction from early chronic phase (ECP) CML patients. Previou s studies have suggested that the Ph-translocation represents a secondary c lonal hit occurring in an already clonally mutated Ph- progenitor or stem c ells, leaving the unanswered question whether Ph- CD34+HLA-DR- progenitors a re norm at. To show the clonal nature of Ph- CD34(+) HLA-DR- CML progenit ors, we have compared the expression of BCR/ABL mRNA with X-chromosome inac tivation patterns (HUMARA) in mononuclear cells and in CD34(+)HLA-DR+ and C D34+HLA-DR- progenitors in marrow and blood obtained from 11 female CML pat ients (8 in chronic phase and 3 in accelerated phase [AP] disease). Steady- state marrow-derived BCR/ABL mRNA(-), CD34(+)HLA-DR- progenitors had polycl onal X-chromosome inactivation patterns in 2 of 2 patients. The same polycl onal pattern was found in the progeny of CD34(+)HLA-DR- derived long-term c ulture-initiating cells. Mobilization with intensive chemotherapy induced a Ph-, BCR/ABL mRNA- and polyclonal state in the CD34(+)HLA-DR- and CD34(+)H LA-DR+ progenitors from 2 ECP patients. In a third ECP patient, polyclonal CD34(+) cells could only be found in the first peripheral blood collection. In contrast to ECP CML, steady-state marrow progenitors in late chronic ph ase and AP disease were mostly Ph+, BCR/ABL mRNA(+), and clonal, Further, i n the majority of these patients, a Ph-, polyclonal state could not be rest ored despite mobilization with intensive chemotherapy, We conclude from the se studies that CD34+HLA-DR- cells that are Ph- and BCR/ABL mRNA- are polyc lonal and therefore benign. This population is suitable for autografting in CML. (C) 1999 by The American Society of Hematology.