IL-6 and MYC collaborate in plasma cell tumor formation in mice

Abstract

IntroductionPlasma cell myeloma (PCM), plasmacytoma (PCT), and immunoglobulin (Ig) deposition diseases belong to a clinically and pathogenetically diverse group of human plasma cell neoplasms (PCNs) composed of fully transformed, Ig-producing B lymphocytes that have undergone terminal differentiation to plasmablasts and plasma cells. Prognosis and outcome of PCM, commonly known as multiple myeloma (MM)-the most prevalent and fatal PCN and the second most common hematologic malignancy worldwide-remain grim despite availability of sophisticated conventional treatment protocols (chemotherapy, irradiation, hematopoietic stem cell transplantation) that have been recently supplemented by novel targeted therapies including proteasome inhibitors (bortezomib), immunomodulatory agents (thalidomide, lenalidomide), antibodies to interleukin-6 (IL-6) or its receptor, and a variety of newly emerging inhibitors of cellular signal transduction pathways. 1 Mouse models of human PCNs may afford a genetically defined and environmentally controlled preclinical research tool for the design and testing of new approaches to prevent, treat, and eventually cure PCM. 2 Furthermore, studies of PCNs in laboratory mice may permit-in ways difficult to pursue in human beingselucidation of the biologic mechanisms by which PCNs originate, progress, and acquire therapy resistance. These considerations underlie the strong rationale to continue with basic research efforts to design new mouse models of PCNs that accurately reproduce important genetic and phenotypic features of their neoplastic human counterparts.Since spontaneous PCNs in laboratory (and wild) mice are rare, 3 efforts have been undertaken to genetically engineer inbred strains of laboratory mice for increased proclivity to malignant plasma cell transformation. The first success along this line took advantage of a v-Abl transgene (TG) expressed in B-lineage cells under control of the intronic immunoglobulin heavy-chain (Igh) enhancer, E. 4 Subsequent approaches relied on TGs, such as E-Bcl2 5 and E-Bcl-X L , 6 that protect incipient plasma cell tumors from programmed cell death (apoptosis). A somewhat unexpected opportunity is afforded by mice harboring a TG fusion gene, NPM-ALK, 7 originally identified as the hallmark mutation of the human T-cell neoplasm, anaplastic large cell lymphoma. A recent, exciting advance is the development of strain Vk*MYC, which is prone to PCM-like tumors induced by a conditional (silent) MYC TG that can be activated in germinal center (GC) B cells upon expression of activation-induced cytidine deaminase (AID). 8 Additional work is warranted to sort out the strengths and limitations of existing TG mouse models and to translate insights gleaned from individual models into tangible benefits for patients with PCNs. Equally important may be the development of new strains that recapitulate PCN traits not produced thus far.One hallmark of human PCN yet to be adequately modeled in mice is the collaboration of the proinflammatory cytokine, interleukin 6 (IL-6), ...

Context-specific roles for paracrine IL-6 in lymphomagenesis

“…IL-6 has been shown to promote T-cell survival both basally and in response to DNA damage Gilbert and Hemann 2010). IL-6 is also a critical survival factor during plasma cell maturation and for the pathogenesis of plasma cell tumors (Beagley et al 1989;Hirano 1991;Hilbert et al 1995;Hideshima et al 2007;Rutsch et al 2010). In nonhematopoietic tissues, IL-6 similarly promotes both cellular survival and tissue repair.…”

Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes

“…Since Myc is known to be involved in the generation of mouse plasmacytomas [34] and other mature neoplasms of mice [35] and humans (such as Burkitt's Lymphoma), it should be able to contribute to the transformation of at least some of the compartments of mature B cells. Our findings that Myc together with Pim1 does not induce long-term proliferation of mature B cells ex vivo or in vivo suggests that different combinations of proto-oncogenes might be active in B-lineage cells at different stages of their development.…”

Preclinical animal models of multiple myeloma

“…The resultant doubletransgenic animals, referred to as C.IL-6/iMyc, demonstrate 100% penetrance with a latency of 3-6 months and phenotypic consistency. 43 Interestingly, 18 F-FDG-PET/CT imaging can be used to monitor tumor progression and response to treatment in this model. 44 Rearrangements of MYC are late progression events in MM that are found in B40% of advanced MM tumors and have welldefined roles in a number of tumor types.…”