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Highly purified primitive hematopoietic stem cells are PML-RARA negative
and generate nonclonal progenitors in acute promyelocytic leukemia
AG Turhan, FM Lemoine, C Debert, ML Bonnet, C Baillou, F Picard, EA Macintyre and B Varet
Service d'Hematologie Adulte, CNRS URA 1461, Paris, France.
The hierarchical level of stem cell involvement in acute promyelocytic
leukemia (APL) characterized by the pathognomonic PML-RARA fusion gene is
unknown. To determine if the cells of the primitive hematopoietic stem cell
compartment are involved in the leukemic process, we have used molecular
and cell sorting techniques in peripheral blood and bone marrow (BM) cells
at diagnosis from three patients with APL and t(15; 17). In two of them,
clonality analysis was also possible using the BstXI polymorphic site of
the PGK gene. The PML-RARA fusion gene was readily identified by reverse
transcriptase-polymerase chain reaction (RT-PCR) analysis of BM cells
obtained at diagnosis in all three patients. These same samples were then
used to sort CD34+ cells and their CD38+ and CD38- subsets by
fluorescence-activated cell sorting. In both female patients, CD34+/CD38+
and CD34+/CD38- cell fractions were polyclonal using PCR, whereas a
monoclonal pattern was identified at the BM sample obtained at diagnosis
either by Southern blotting or by PCR. Because of the high sensitivity of
the PCR analysis, the polyclonal pattern of these cell populations could
mask the presence of a minor clone. To detect this clone, we preformed
RT-PCR analysis for t(15; 17). In one female patient, the abnormal PML-RAR
fusion gene was found only in the more mature CD34+/CD38+ cell fraction
using a nested PCR approach, whereas the polyclonal CD34+/CD38- fraction
was PML-RARA negative. These findings were confirmed in a third patient
with APL in whom the PML-RARA transcripts were absent in the CD34+/CD38-
cell fraction. To study the clonality at the level of clonogenic
progenitors, we used in one patient PGK analysis by PCR of individual
burst-forming units-erythroid and colony-forming units-granulocyte-
macrophage obtained from the CD34+/CD38- and CD34+/CD38+ cell populations
at diagnosis and from the BM sample obtained during remission. The two
highly purified cell populations gave rise to morphologically normal
colonies clonal for both the BstXI site containing (A) and the BstXI site
lacking (B) PGK allelles, indicating their polyclonal content, a pattern
that was also found in clonogenic progenitors obtained at remission. These
findings strongly suggest that the primitive hematopoietic stem cells as
defined by the CD34+/CD38- antigens are not involved by the neoplastic
process in APL. These results may have important implications for
autografting strategies of retinoic acid/chemotherapy-resistant or relapsed
patients.
Volume 85,
Issue 8,
pp. 2154-2161,
04/15/1995
Copyright © 1995 by The American Society of Hematology
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