Gene Expression Profiles in Myeloma: Ready for the Real World?

Szalat, Raphaël; Avet-Loiseau, Hervé; Munshi, Nikhil C.

doi:10.1158/1078-0432.ccr-16-0867

Cited by 56 publications

(46 citation statements)

References 82 publications

(81 reference statements)

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“…Several gene-expression profiling analyses of primary MM cells have led to a molecular classification of MM subtypes (32–34). This classification now includes 8 subgroups characterized either by an IgH translocation with the CyclinD1 [ t (11;14) ; CCND1 group], the MMSET oncogene [ t (4;14) ; MS group], MAF oncogenes [ t (14;16) and t (14;20) ], or by specific gene signatures (PR, HY, Myeloid, SOCS3, and NFKB) (35, 36). We previously reported the apoptotic machinery diversity in MM major subgroups (HY, CCND1, MF, and MS) (37).…”

Section: Resultsmentioning

confidence: 99%

BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker

et al. 2019

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BCL2-family proteins have a central role in the mitochondrial apoptosis machinery and their expression is known to be deregulated in many cancer types. Effort in the development of small molecules that selectively target anti-apoptotic members of this family i.e., Bcl-2, Bcl-xL, Mcl-1 recently opened novel therapeutic opportunities. Among these apoptosis-inducing agents, BH3-mimetics (i.e., venetoclax) led to promising preclinical and clinical activity in B cell malignancies. However, several mechanisms of intrinsic or acquired resistance have been described ex vivo therefore predictive markers of response as well as mechanism-based combinations have to be designed. In the present study, we analyzed the expression of the BCL2-family genes across 10 mature B cell malignancies through computational normalization of 21 publicly available Affimetrix datasets gathering 1,219 patient samples. To better understand the deregulation of anti- and pro-apoptotic members of the BCL2-family in hematological disorders, we first compared gene expression profiles of malignant B cells to their relative normal control (naïve B cell to plasma cells, n = 37). We further assessed BCL2-family expression according to tissue localization i.e., peripheral blood, bone marrow, and lymph node, molecular subgroups or disease status i.e., indolent to aggressive. Across all cancer types, we showed that anti-apoptotic genes are upregulated while pro-apoptotic genes are downregulated when compared to normal counterpart cells. Of interest, our analysis highlighted that, independently of the nature of malignant B cells, the pro-apoptotic BH3-only BCL2L11 and PMAIP1 are deeply repressed in tumor niches, suggesting a central role of the microenvironment in their regulation. In addition, we showed selective modulations across molecular subgroups and showed that the BCL2-family expression profile was related to tumor aggressiveness. Finally, by integrating recent data on venetoclax-monotherapy clinical activity with the expression of BCL2-family members involved in the venetoclax response, we determined that the ratio (BCL2+BCL2L11+BAX)/BCL2L1 was the strongest predictor of venetoclax response for mature B cell malignancies in vivo.

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Section: Resultsmentioning

confidence: 99%

BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker

et al. 2019

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“…However, its expression was markedly increased in patients with symptomatic MM and with disease progression from TT2 (TT + thalidomide) to TT3 (TT2 + bortezomib), as well as from newly diagnosed MM to relapsed/refractory MM (Figure S1A). Moreover, high‐risk subsets (MF [ MAF / MAFB ], MS [ MMSET ], PR [proliferation]) exhibited significantly higher ARNT expression than low‐risk ones (CD‐1 [ CCND1 / CCND3 ‐1], CD‐2 [ CCND1 / CCND3 ‐2], HY [hyperdiploid], LB [low bone disease]; Figure 1B), according to the molecular criteria for risk stratification 31, 32S1B) and t [14,16] ( MAF + ; Figure S1C) or 17p deletion ( TP53 + ; Figure S1D), respectively ( P < .05 for each case).…”

Section: Resultsmentioning

confidence: 99%

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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“…Early detection and diagnosis of MM could significantly decrease mortality from the disease. The majority of current biomarker studies have focused on gene or protein expression in serum from patients with MM (19,20). However, these markers cannot indicate the BM microenvironment, especially for patients at early stages of MM (19).…”

Section: Discussionmentioning

confidence: 99%

Identification of glutathione S‑transferase π 1 as a prognostic proteomic biomarker for multiple myeloma using proteomic profiling

Zhao

Wang

et al. 2020

Oncol Lett

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Multiple myeloma (MM) is a B-cell hematological malignancy with monoclonal plasma cell proliferation in the bone marrow. Early diagnosis of MM remains difficult due to the lack of specific symptoms and biomarkers. In the present study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the ClinProt system was used to detect potential biomarkers for MM from the bone marrow samples of 30 patients and 30 healthy controls. A total of 10 of the most significantly differentiated peaks between the patients and controls were identified. When patients with MM were compared with controls, 6 peaks with m/z values

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Gene Expression Profiles in Myeloma: Ready for the Real World?

Cited by 56 publications

References 82 publications

BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker

BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Identification of glutathione S‑transferase π 1 as a prognostic proteomic biomarker for multiple myeloma using proteomic profiling

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