KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

SIMPLE SUMMARY: KRAS and genes in the RAS-MAPK pathway are among the most frequently deregulated genes in solid tumors and in this context a large amount of KRAS and RAS-MAPK targeting molecules have been developed and tested. The improved understanding of genomic variation in mature B cell neoplasms revealed a considerable portion of patients presenting with KRAS or RAS-MAPK pathway aberrations. These patients could potentially benefit from the use of RAS-RAF-MEK-ERK inhibitors, and in most of the cases, clinical investigation is only in the beginning. Here, we review the incidence of KRAS and RAS-MAPK mutations in mature B cell lymphoproliferative disorders, their association with progression and survival, and current therapeutic strategies targeting RAS-MAPK signaling. ABSTRACT: KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology.