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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2913-2921
Analysis of the biologic properties of p230 Bcr-Abl reveals unique
and overlapping properties with the oncogenic p185 and p210 Bcr-Abl
tyrosine kinases
Robert C. Quackenbush,
Gary W. Reuther,
Juli P. Miller,
Kevin D. Courtney,
Warren S. Pear, and
Ann Marie Pendergast
From the Department of Pharmacology and Cancer Biology and the
Divisions of Hematology and Oncology, Department of Medicine, Duke
University Medical Center, Durham, NC; and the Department of Pathology
and Institute for Medicine and Engineering, University of Pennsylvania,
Philadelphia, PA.
The reciprocal translocation between chromosomes 9 and 22 that fuses
coding sequences of the Bcr and Abl genes is responsible for a
remarkably diverse group of hematologic malignancies. A newly described
230-kd form of Bcr-Abl has been associated with an indolent
myeloproliferative syndrome referred to as chronic neutrophilic
leukemia. We have cloned the corresponding gene and examined the
biologic and biochemical properties of p230 Bcr-Abl after
retroviral-mediated gene transfer into hematopoietic cell lines and
primary bone marrow cells. p230 Bcr-Abl-expressing 32D myeloid cells
were fully growth factor-independent and activated similar signal
transduction pathways as the well-characterized p210 and p185 forms of
Bcr-Abl. In contrast, primary mouse bone marrow cells expressing p230
required exogenous hematopoietic growth factors for optimal growth,
whereas p185- and p210-expressing cells were independent of growth
factors. The 3 Bcr-Abl proteins exerted different effects on
differentiation of bone marrow cells. p185 induced outgrowth of
lymphoid precursors capable of tumor formation in immunodeficient mice.
In contrast, p210- and p230-expressing bone marrow cells caused limited
outgrowth of lymphoid precursors that failed to form tumors in
immunodeficient mice. Removal of cytokines and autologous stroma from
Bcr-Abl-expressing bone marrow cultures produced the expansion of
distinct lineages by the various Bcr-Abl proteins. p185 drove expansion
of cytokine-independent lymphoid progenitors, while p210 and p230
generated cytokine-independent monocyte/myeloid cells. These findings
suggest that the different Bcr-Abl fusion proteins drive the expansion
of different hematopoietic populations, which may explain the
association of the various Bcr-Abl oncoproteins with different spectra
of human leukemias.
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