The SH3 domain contributes to BCR/ABL-dependent leukemogenesis in vivo: Role in adhesion, invasion, and homing

被引:75
作者
Skorski, T
Nieborowska-Skorska, M
Wlodarski, P
Wasik, M
Trotta, R
Kanakaraj, P
Salomoni, P
Antonyak, M
Martinez, R
Majewski, M
Wong, A
Perussia, B
Calabretta, B
机构
[1] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Inst, Philadelphia, PA 19107 USA
[2] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
关键词
D O I
10.1182/blood.V91.2.406.406_406_418
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (Delta SH3 BCR/ABL) constitutively expressed in murine hematopoietic cells. Delta 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 Delta SH3 BCR/ABL protected 320cl3 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 Delta 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 Delta 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 alpha 2 integrin by Delta SH3 BCR/ABL-transfected 32Dcl3 cells. Moreover, as compared with wild-type BCR/ABL, which localizes primarily in the cytoskeletal/membrane fraction, Delta 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. (C) 1998 by The American Society of Hematology.
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页码:406 / 418
页数:13
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