title: Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia.
abstract: The Rac family of small Rho GTPases coordinates diverse cellular functions in hematopoietic cells including adhesion, migration, cytoskeleton rearrangements, gene transcription, proliferation, and survival. The integrity of Rac signaling has also been found to critically regulate cellular functions in the initiation and maintenance of hematopoietic malignancies. Using an in vivo gene targeting approach, we demonstrate that Rac2, but not Rac1, is critical to the initiation of acute myeloid leukemia in a retroviral expression model of MLL-AF9 leukemogenesis. However, loss of either Rac1 or Rac2 is sufficient to impair survival and growth of the transformed MLL-AF9 leukemia. Rac2 is known to positively regulate expression of Bcl-2 family proteins toward a prosurvival balance. We demonstrate that disruption of downstream survival signaling through antiapoptotic Bcl-2 proteins is implicated in mediating the effects of Rac2 deficiency in MLL-AF9 leukemia. Indeed, overexpression of Bcl-xL is able to rescue the effects of Rac2 deficiency and MLL-AF9 cells are exquisitely sensitive to direct inhibition of Bcl-2 family proteins by the BH3-mimetic, ABT-737. Furthermore, concurrent exposure to NSC23766, a small-molecule inhibitor of Rac activation, increases the apoptotic effect of ABT-737, indicating the Rac/Bcl-2 survival pathway may be targeted synergistically.
authors.affiliation: Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, OH 45229, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mizukawa
authors.forename: Junping
authors.initials: J
authors.lastname: Wei
authors.forename: Mahesh
authors.initials: M
authors.lastname: Shrestha
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Chou
authors.forename: Andrea
authors.initials: A
authors.lastname: Griesinger
authors.forename: Chad E
authors.initials: CE
authors.lastname: Harris
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000634:Aminoquinolines; D001713:Biphenyl Compounds; D009479:Neuropeptides; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013449:Sulfonamides; D051020:bcl-X Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C501332:ABT-737; C494812:Bcl2l1 protein, mouse; C487513:NSC 23766; C484602:Rac1 protein, mouse