title: The SH3 domain contributes to BCR/ABL-dependent leukemogenesis in vivo: role in adhesion, invasion, and homing.
abstract: 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 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 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.
authors.affiliation: Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: T
authors.initials: T
authors.lastname: Skorski
authors.forename: M
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: P
authors.initials: P
authors.lastname: Wlodarski
authors.forename: M
authors.initials: M
authors.lastname: Wasik
authors.forename: R
authors.initials: R
authors.lastname: Trotta
authors.forename: P
authors.initials: P
authors.lastname: Kanakaraj
authors.forename: P
authors.initials: P
authors.lastname: Salomoni
authors.forename: M
authors.initials: M
authors.lastname: Antonyak
authors.forename: R
authors.initials: R
authors.lastname: Martinez
authors.forename: M
authors.initials: M
authors.lastname: Majewski
authors.forename: A
authors.initials: A
authors.lastname: Wong
authors.forename: B
authors.initials: B
authors.lastname: Perussia
authors.forename: B
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D007942:Leukemia, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D016044:Fusion Proteins, bcr-abl