Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 284-292
BCR/ABL
CD34+HLA-DR
Progenitor Cells in Early Chronic Phase, But Not in More Advanced
Phases, of Chronic Myelogenous Leukemia Are Polyclonal
Michel Delforge,
Marc A. Boogaerts,
Philip B. McGlave, and
Catherine M. Verfaillie
From the Division of Hematology, the Department of Medicine,
University Hospital Gasthuisberg, Leuven, Belgium; and the
Division of Hematology, the Department of Medicine, University of
Minnesota, Minneapolis.
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 restored in vivo after
treatment with 
-interferon or intensive chemotherapy, suggesting
that normal stem and progenitor cells coexist with the
Ph+ clone. We have previously shown that
Ph progenitors are highly enriched in the
CD34+HLA-DR fraction from early chronic
phase (ECP) CML patients. Previous studies have suggested that the
Ph-translocation represents a secondary clonal hit occurring in an
already clonally mutated Ph progenitor or stem cells,
leaving the unanswered question whether Ph
CD34+HLA-DR- progenitors are normal. To show
the clonal nature of Ph
CD34+HLA-DR CML progenitors, we have
compared the expression of BCR/ABL mRNA with X-chromosome inactivation
patterns (HUMARA) in mononuclear cells and in
CD34+HLA-DR+ and
CD34+HLA-DR progenitors in marrow and
blood obtained from 11 female CML patients (8 in chronic phase and 3 in
accelerated phase [AP] disease). Steady-state marrow-derived BCR/ABL
mRNA, CD34+HLA-DR
progenitors had polyclonal X-chromosome inactivation patterns in 2 of 2 patients. The same polyclonal pattern was found in the progeny of
CD34+HLA-DR derived long-term
culture-initiating cells. Mobilization with intensive
chemotherapy induced a Ph, BCR/ABL mRNA
and polyclonal state in the CD34+HLA-DR
and CD34+HLA-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
phase and AP disease were mostly Ph+, BCR/ABL
mRNA+, and clonal. Further, in the majority of these
patients, a Ph, polyclonal state could not be restored
despite mobilization with intensive chemotherapy. We conclude from
these studies that CD34+HLA-DR cells that
are Ph and BCR/ABL mRNA are polyclonal
and therefore benign. This population is suitable for autografting in
CML.
