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The SH3 Domain Contributes to BCR/ABL-Dependent Leukemogenesis In
Vivo: Role in Adhesion, Invasion, and Homing
Tomasz Skorski,
Malgorzata Nieborowska-Skorska,
Pawel Wlodarski,
Mariusz Wasik,
Rossana Trotta,
Palanisamy Kanakaraj,
Paolo Salomoni,
Mark Antonyak,
Robert Martinez,
Miroslaw Majewski,
Albert Wong,
Bice Perussia, and
Bruno Calabretta
From the Kimmel Cancer Institute, Jefferson Medical College,
Philadelphia, PA; and the Department of Pathology and Laboratory
Medicine, University of Pennsylvania, Philadelphia, PA.
To determine the possible role of the BCR/ABL oncoprotein SH3 domain
in BCR/ABL-dependent leukemogenesis, we studied the biologic properties
of a BCR/ABL SH3 deletion mutant ( SH3 BCR/ABL) constitutively expressed in murine hematopoietic cells. SH3 BCR/ABL was able to
activate known BCR/ABL-dependent downstream effector molecules such as
RAS, PI-3kinase, MAPK, JNK, MYC, JUN, STATs, and BCL-2. Moreover,
expression of SH3 BCR/ABL protected 32Dcl3 murine myeloid precursor
cells from apoptosis, induced their growth factor-independent proliferation, and resulted in transformation of primary bone marrow
cells in vitro. Unexpectedly, leukemic growth from cells expressing
SH3 BCR/ABL was significantly retarded in SCID mice compared with
that of cells expressing the wild-type protein. In vitro and in vivo
studies to determine the adhesive and invasive properties of SH3
BCR/ABL-expressing cells showed their decreased interaction to collagen
IV- and laminin-coated plates and their reduced capacity to invade the
stroma and to seed the bone marrow and spleen. The decreased
interaction with collagen type IV and laminin was consistent with a
reduced expression of  2 integrin by SH3 BCR/ABL-transfected
32Dcl3 cells. Moreover, as compared with wild-type BCR/ABL, which
localizes primarily in the cytoskeletal/ membrane fraction, SH3
BCR/ABL was more evenly distributed between the cytoskeleton/membrane
and the cytosol compartments. Together, the data indicate that the SH3
domain of BCR/ABL is dispensable for in vitro transformation of
hematopoietic cells but is essential for full leukemogenic potential in
vivo.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 406-418
© 1998 by The American Society of Hematology.
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