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Differentiation-associated changes in CD44 isoform expression during normal
hematopoiesis and their alteration in chronic myeloid leukemia
S Ghaffari, GJ Dougherty, PM Lansdorp, AC Eaves and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
CD44 is a widely expressed, multifunctional, cell-surface glycoprotein that
has been implicated in the regulation of normal hematopoiesis. In addition,
expression of particular isoforms of CD44 has been associated with
malignant transformation and/or the acquisition of metastatic potential. In
this study, we used two recently developed monoclonal anti-CD44 antibodies,
one reactive with an epitope shared by many CD44 isoforms and the other
with an epitope unique to CD44 isoforms containing amino acids encoded by
the alternatively spliced exon v10, to compare the expression of CD44 on
primitive hematopoietic cells from the marrow of normal individuals and
their neoplastic counterparts present in the peripheral blood of patients
with chronic myeloid leukemia (CML). Multiparameter fluorescence-activated
cell sorter (FACS) analysis and cell sorting studies showed that CD44 is
normally expressed at high to very high levels on both long-term culture-
initiating cells (LTC-IC) and granulopoietic colony-forming cells
(granulocyte-macrophage colony-forming units [CFU-GM]). In contrast,
primitive erythropoietic progenitors (burst-forming units-erythroid
[BFU-E]) in normal marrow were more homogeneous in their expression of
CD44, and very few (less than 5%) showed the very high levels of CD44 seen
on 20% to 25% of LTC-IC and CFU-GM. Antibody staining showed the expression
of exon v10-containing CD44 isoforms to be restricted to a small
subpopulation (4% to 8%) of morphologically recognizable mature (CD34-)
myeloid cells within the light-density fraction of normal marrow cells.
Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed
the presence of two exon v10-containing mRNA species. In CML, a
significantly greater proportion of the circulating neoplastic CFU-GM
expressed very high levels of CD44, and these CFU-GM were accompanied by an
increased number of light density v10+ cells, including some that
coexpressed CD34. Nonmalignant hematopoietic progenitors mobilized by prior
chemotherapy and growth factor treatment of patients with Hodgkin's disease
or acute myeloid leukemia in remission showed no changes in CD44 expression
relative to normal marrow progenitors. These results provide evidence of
early differentiation-associated changes in CD44 expression during normal
hematopoiesis in vivo that may be deregulated in the neoplastic clone of
patients with CML.
Volume 86,
Issue 8,
pp. 2976-2985,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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