المؤلفون: Samuel A Danziger, Mark McConnell, Jake Gockley, Mary H Young, Adam Rosenthal, Frank Schmitz, David J Reiss, Phil Farmer, Daisy V Alapat, Amrit Singh, Cody Ashby, Michael Bauer, Yan Ren, Kelsie Smith, Suzana S Couto, Frits van Rhee, Faith Davies, Maurizio Zangari, Nathan Petty, Robert Z Orlowski, Madhav V Dhodapkar, Wilbert B Copeland, Brian Fox, Antje Hoering, Alison Fitch, Katie Newhall, Bart Barlogie, Matthew W B Trotter, Robert M Hershberg, Brian A Walker, Andrew P Dervan, Alexander V Ratushny, Gareth J Morgan

المصدر: PLoS Medicine, Vol 17, Iss 11, p e1003323 (2020)

مصطلحات موضوعية: Medicine

الوصف: BackgroundThe tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases.Methods and findingsBetween 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies.ConclusionsIn this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1549-1277Test; https://doaj.org/toc/1549-1676Test

الوصول الحر: https://doaj.org/article/48a59d8f2fb64baa9b747522459ffea9Test

المؤلفون: Dongmin Gu, Shuhong Wang, Isere Kuiatse, Hua Wang, Jin He, Yun Dai, Richard J Jones, Chad C Bjorklund, Jing Yang, Steven Grant, Robert Z Orlowski

المصدر: PLoS ONE, Vol 9, Iss 9, p e103015 (2014)

مصطلحات موضوعية: Medicine, Science

الوصف: Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC4151993?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/a959e105d182485e9a7593077f2e8915Test

المؤلفون: Xin-Yan Pei, Yun Dai, Jessica Felthousen, Shuang Chen, Yukie Takabatake, Liang Zhou, Leena E Youssefian, Michael W Sanderson, Wesley W Bodie, Lora B Kramer, Robert Z Orlowski, Steven Grant

المصدر: PLoS ONE, Vol 9, Iss 3, p e89064 (2014)

مصطلحات موضوعية: Medicine, Science

الوصف: The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3942309?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/3c9abcdb83b1404890faef5d609aa231Test