Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Author:

Chang Kyung Hee12,Sanchez-Aguilera Abel3,Shen Shuhong4,Sengupta Amitava1,Madhu Malav N.1,Ficker Ashley M.1,Dunn Susan K.2,Kuenzi Ashley M.1,Arnett Jorden L.1,Santho Rebecca A.1,Agirre Xabier5,Perentesis John P.6,Deininger Michael W.7,Zheng Yi1,Bustelo Xose R.8,Williams David A.3,Cancelas Jose A.12

Affiliation:

1. Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;

2. Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH;

3. Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;

4. Department of Hematology/Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University Medical School, Shanghai, China;

5. Hematology Department and Area of Cell Therapy, Foundation for Applied Medical Research, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain;

6. Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;

7. Division of Hematology and Hematologic Malignancies, University of Utah Huntsman Cancer Institute, Salt Lake City, UT; and

8. Centro de Investigación del Cáncer, University of Salamanca, Campus Unamuno, Salamanca, Spain

Abstract

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–expressng acute lymphoblastic leukemia.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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