Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

Lohr, Jens G.; Stojanov, Petar; Carter, Scott L.; Cruz‐Gordillo, Peter; Lawrence, Michael S.; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A.; Straussman, Ravid; Levy, Joan; Perkins, Louise M.; Keats, Jonathan J.; Schumacher, Steven E.; Rosenberg, Mara; Getz, Gad; Golub, Todd R.; Anderson, Kenneth C.; Richardson, Paul G.; Krishnan, Amrita; Lonial, Sagar; Kaufman, Jonathan L.; Siegel, David S.; Vesole, David H.; Roy, Vivek; Rivera, Candido E.; Rajkumar, S. Vincent; Kumar, Shaji; Fonseca, Rafaël; Ahmann, Greg; Bergsagel, P. Leif; Stewart, A. Keith; Hofmeister, Craig C.; Efebera, Yvonne A.; Jagannath, Sundar; Chari, Ajai; Trudel, Suzanne; Reece, Donna; Wolf, Jeffrey; Martin, Thomas; Zimmerman, Todd; Rosenbaum, Cara A.; Jakubowiak, Andrzej; Lebovic, Daniel; Vij, Ravi; Stockerl‐Goldstein, Keith

doi:10.1016/j.ccr.2013.12.015

Cited by 852 publications

(988 citation statements)

References 52 publications

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“…S8). Interestingly, analysis of primary MM exome sequencing data from Lohr et al (2) revealed that RNF43 and ZNRF3, the E3 ligases that are subject to inhibition by LGR/ R-spondin signaling, harbor mutations in primary MM at low frequency (together 4/203, 2%). Mutations in these genes have been shown to drive Wnt signaling in other tumors (17)(18)(19); however, the effect of these specific mutations on Wnt signaling in MM remains to be established.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the wide variety of underlying structural and numerical genomic abnormalities (1)(2)(3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.…”

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confidence: 99%

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Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Recurrent missense EGR2 mutations affect DNA binding and transcriptional activity of the protein but the precise consequences on cellular biology are not known [73]. Missense EGR1 mutations are recurrently observed in myeloma, but not functionally characterized [79]. BRAF encodes a Ser/Thr kinase that mediates signal transduction along many intracellular pathways [80].…”

Section: Implication Of the Bcr Tlr Pathwaysmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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“…For example, BRAF, KRAS, and NRAS mutations can be subclonal in multiple myeloma, and the use of BRAF inhibitors can activate ERK signaling in BRAF wild-type cells [59]. A computational prediction used to optimize therapeutic combinations specifically to treat tumor heterogeneity found that knowledge of the dominant subclones alone is often insufficient for selecting certain drug combinations.…”

Section: Challenge: Drug Resistance and The Role Of Tumor Genetic DIVmentioning

confidence: 99%

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Kemp

Shim

Heo

et al. 2016

Advanced Drug Delivery Reviews

416

258

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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

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Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

Cited by 852 publications

References 52 publications

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Chronic lymphocytic leukemia: Time to go past genomics?

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

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