Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival.
Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressing acute lymphoblastic leukemia.
Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
Kyung Hee
KH
Chang
Abel
A
Sanchez-Aguilera
Shuhong
S
Shen
Amitava
A
Sengupta
Malav N
MN
Madhu
Ashley M
AM
Ficker
Susan K
SK
Dunn
Ashley M
AM
Kuenzi
Jorden L
JL
Arnett
Rebecca A
RA
Santho
Xabier
X
Agirre
John P
JP
Perentesis
Michael W
MW
Deininger
Yi
Y
Zheng
Xose R
XR
Bustelo
David A
DA
Williams
Jose A
JA
Cancelas
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D015996:Survival Rate; D014410:Tumor Stem Cell Assay; D020744:rac GTP-Binding Proteins / Q000502:physiology; D000097766:RAC2 GTP-Binding Protein
D016044:Fusion Proteins, bcr-abl; D051567:Proto-Oncogene Proteins c-vav; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse