Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras

Abstract

genes are mutated in 5%-40% of a spectrum of myeloid and lymphoid cancers with affected 2-3 times more often than Genomic analysis indicates that mutations generally occur as secondary events in leukemogenesis, but are integral to the disease phenotype. The tractable nature of the hematopoietic system has facilitated generating accurate mouse models of hematologic malignancies characterized by hyperactive Ras signaling. These strains provide robust platforms for addressing how oncogenics expression perturbs proliferation, differentiation, and self-renewal programs in stem and progenitor cell populations, for testing potential therapies, and for investigating mechanisms of drug response and resistance. This review summarizes recent insights from key studies in mouse models of hematologic cancer that are broadly relevant for understanding Ras biology and for ongoing efforts to implement rational therapeutic strategies for cancers with oncogenic mutations.

Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia

“…Here, we present data describing the effects of RGS, a small molecule RAS mimetic [6], as a therapeutic agent in a pre-clinical mouse model of KRAS G12D -driven MPN. Previous studies using compound genetically modified mouse models and small molecule inhibitors have highlighted the utility of inhibiting downstream effectors of RAS proteins in the treatment of RAS-driven myeloid malignancies [1, 2, 19, 20, 27–29]. In these instances, overall survival, as well as both disease burden and malignant phenotypes, were dramatically improved, demonstrating that blocking signals that are transmitted downstream of RAS has the potential to be clinically beneficial, even in the absence of elimination of the malignant clone.…”

“…Somatic mutations of RAS genes are present in approximately 5-40% of hematological malignancies and often arise as secondary events that cooperate with other driver mutations [1,2]. In addition to mutation of RAS genes themselves, mutation of genes such as PTPN11 or NF1 often result in a loss of negative regulatory cues and ultimately lead to hyperactivation of RAS-driven signaling [1,2].…”

“…Somatic mutations of RAS genes are present in approximately 5-40% of hematological malignancies and often arise as secondary events that cooperate with other driver mutations [1,2]. In addition to mutation of RAS genes themselves, mutation of genes such as PTPN11 or NF1 often result in a loss of negative regulatory cues and ultimately lead to hyperactivation of RAS-driven signaling [1,2]. Of the myeloid malignancies that harbor RAS mutations or exhibit abnormally high levels of RAS activity, juvenile myelomonocyitc leukemia (JMML), an aggressive and rare childhood cancer [3], almost invariably (~90%) presents with driver mutations in KRAS , NRAS or other genes encoding RAS pathway regulatory proteins [4, 1,5].…”

“…In addition to mutation of RAS genes themselves, mutation of genes such as PTPN11 or NF1 often result in a loss of negative regulatory cues and ultimately lead to hyperactivation of RAS-driven signaling [1,2]. Of the myeloid malignancies that harbor RAS mutations or exhibit abnormally high levels of RAS activity, juvenile myelomonocyitc leukemia (JMML), an aggressive and rare childhood cancer [3], almost invariably (~90%) presents with driver mutations in KRAS , NRAS or other genes encoding RAS pathway regulatory proteins [4, 1,5]. The high frequency of these genomic alterations suggests that targeting RAS signaling, either by inhibiting RAS proteins themselves, their effectors, or regulators, might be an effective strategy to combat this and other myeloid malignancies that are RAS pathway-dependent.…”

Noncoding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies

“…To determine the efficacy of enCRISPRi/a across cell lines, we performed similar analyses in MOLM-13 AML and Jurkat ALL cells. We found that 13 of 14 genes were significantly repressed in AML (MKPL-1 and MOLM13) and ALL (Jurkat) cells by enCRISPRi (≥ 2-fold, P < 0.05), and Activating mutations in KRAS are common in solid tumors but relatively rare in hematologic malignancies (30,31); however, KRAS expression is increased and associates with poor survival in AML patients (Fig. S8A,B).…”