Abstract
Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (KrasG12D) activated specifically in germinal center B-cells. We also generated mice with activation of the KrasG12D allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.
Highlights
Multiple myeloma (MM) is an incurable malignancy of antibody-secreting plasma B-cells, whose etiology remains poorly understood
We confirmed Cre-recombination in vivo in mature B-cell populations isolated from Cc1-Cre KrasG12D mice by fluorescence associated cell sorting (FACS)
Kras is the oncogene most frequently mutated in MM, yet its role in the pathogenesis of the disease has yet to be elucidated
Summary
Multiple myeloma (MM) is an incurable malignancy of antibody-secreting plasma B-cells, whose etiology remains poorly understood. Using a targeted sequencing approach to screen highly expressed tyrosine kinase and cytokine signaling genes in primary human patient myeloma, we previously identified mutations at codon 12 and 61 in N- and KRAS as being the only recurrent variation in our sample set [4]. The somatic SNVs found most frequently in MM are gain-of-function mutations in Ras oncogenes (Kras and Nras), causing constitutive activation of the Ras protein [5]. Despite the genomic evidence for Ras pathogenesis, the functional role of Ras activation in MM has not previously been tested. This issue is not trivial as the induction of neoplasia by Ras activation is highly dependent on cellular context [6]. Pharmaceutical approaches to target cancers with mutant Ras are underway [7,8,9,10], and a pre-clinical model faithfully replicating Ras-driven myeloma would be critical in evaluating the therapeutic potential of these agents in myeloma
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