Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease

Abstract

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

“…11 However, intrinsic problems associated with gene expression of a retroviral-driven oncogene and premature death of retrovirally transduced/transplanted mice precluded the analysis of the function of Rac2 in LSC/P in vivo. Leukemic development progresses slowly in FVB/N ϫ C57Bl/6 Scl/p210 mice (50% mortality after 8 months; Figure 1A) allowing the analysis of LSC/P progressive disease.…”

“…9,10 Using a retroviral transduction model, we showed that the deficiency of the hematopoietic-specific Rac2 GTPase, but not Rac1 alone, prolonged survival of mice with myeloproliferative disease (MPD). 11 However, rapid-progressing leukemia within a relatively shorter latency hindered analysis of CML-initiating and propagating stem cells during the disease development in vivo.…”

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

“…In a colorectal carcinoma model involving orthotopic injection of adenocarcinoma cells into mice, Rac1 overexpression promoted, and Rac1 knockdown decreased tumor progression (Espina et al, 2008). More recently, activation of Rac proteins was described to be crucial for the development of chronic myelogenous leukemia (Thomas et al, 2007) and K-Ras-induced lung cancer (Kissil et al, 2007). Indirect evidence also suggested a role for Rac1 in skin tumor formation, as mice lacking the Rac1-specific GEF Tiam1, which display about 50% reduction in GTP-bound Rac1, are rather resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation (Malliri et al, 2002).…”

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

“…For example, in chronic lymphocytic leukemia, Rac1 activity is increased but no changes in its expression levels have been reported. 11 Recently, human exome sequencing analysis in melanomas have identified Rac1 and Cdc42 somatic mutations which conferred increased activities 12,13 suggesting, that like Ras, point mutations might be sufficient to promote tumorigenesis in some cases. Finally, altering Rho-GEFs, Rho-GAPs or Rho-GDIs expression or function may also be sufficient to modulate Rho GTPase activity and participate to tumor development.…”