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Article
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Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open Access
The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open Access
Multi-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features
The characterisation of the molecular features of multiple myeloma (MM) remains challenging. Here, the authors identify a subset of MM patients with a dismal clinical outcome, harbouring both chromosomes 1q CN gain and 13 CN loss and overexpressing CCND2.
- Carolina Terragna
- , Andrea Poletti
- & Michele Cavo
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Article
| Open Access
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open Access
Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth
BCMA-specific CAR T-cell therapies have shown high response rates in multiple myeloma (MM), however the majority of patients still relapse. Here the authors show that CD24-positive MM cells increase after BCMA-CAR-T treatment in patients, and that dual-targeted BCMA/CD24 CAR-T cells can improve anti-tumor efficacy in MM preclinical models.
- Fumou Sun
- , Yan Cheng
- & Fenghuang Zhan
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Article
| Open Access
Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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Article
| Open Access
Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma
Patients with myeloma multiple treated with BCMA CAR T cells often relapse with BCMA-negative disease or antigen escape. Here the authors describe the design of TACI-directed single and dual CAR T cells with in vitro and in vivo activity against multiple myeloma, overcoming BCMA antigen loss.
- Rebecca C. Larson
- , Michael C. Kann
- & Marcela V. Maus
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Article
| Open Access
Disentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study
Multiple myeloma (MM) is a haematological malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS). Here, the authors use a mechanistic model fitted to surveillance data from the United States to investigate whether variation in MM is best explained by incidence of MGUS or rate of progression to MM.
- John H. Huber
- , Mengmeng Ji
- & Su-Hsin Chang
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| Open Access
Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance
Myelomagenesis progresses through well-defined pre-malignant states. Here, using single-cell RNA sequencing and T cell receptor repertoire analysis of bone marrow T cells in patients at different stages of myelomagenesis, the authors identify large clonotypic expansions characterized by the expression of multiple immune checkpoints.
- Cirino Botta
- , Cristina Perez
- & Bruno Paiva
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Article
| Open Access
Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma
How the immune response is involved in the response to multiple myeloma after treatment is not fully understood. Here the authors investigate how lenalidomide treatment in newly diagnosed MM patients affects the immune microenvironment in the blood and bone marrow and compare between responses to treatment.
- David G. Coffey
- , Francesco Maura
- & Ola Landgren
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Article
| Open Access
Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level
The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.
- Lukas John
- , Alexandra M. Poos
- & Niels Weinhold
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Article
| Open Access
The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease
Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Here, the authors demonstrate that the checkpoint inhibitor PD-1H functions as a potential MMP-13 receptor on osteoclasts, mediating MMP-13 induced cytoskeleton reorganization, fusogenesis and bone resorption and further regulating osteolytic lesions.
- Jing Fu
- , Shirong Li
- & Suzanne Lentzsch
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Article
| Open Access
Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma
Patients treated for multiple myeloma often experience relapse due to antigen loss, thus necessitating the identification of additional therapeutic targets. In this study, the authors demonstrate that FcRH5 is expressed on MM cells and can be targeted using chimaeric antigen receptor T cells in mice.
- Dongpeng Jiang
- , Haiwen Huang
- & Jianhong Chu
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Article
| Open Access
Excessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma
The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.
- Chunmei Kuang
- , Meijuan Xia
- & Wen Zhou
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Article
| Open Access
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open Access
Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance
The molecular mechanisms underlying acquired chemoresistance to proteasome inhibitors (PIs) in multiple myeloma (MM) remain to be explored. Here, the authors highlight the role of heterochromatin protein 1 gamma as a potential target for overcoming resistance to PIs in MM.
- Xin Li
- , Sheng Wang
- & Zhiqiang Liu
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Article
| Open Access
Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open Access
Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis
Development of multiple myeloma is preceded by precursor conditions. Here, the authors use single cell RNA-sequencing of plasma cells from patients across disease stages to identify genomic signatures present even at the earliest stages of disease.
- Rebecca Boiarsky
- , Nicholas J. Haradhvala
- & Gad Getz
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Article
| Open Access
The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma
Development of proteasome inhibitor resistance is a common problem in patients with multiple myeloma. Here, the authors show that deubiquitinase OTUD1 protects PRDX4 from degradation resulting in increased load of misfolded immunoglobulins sensitizing myeloma cells for proteasome inhibition.
- Alexander Vdovin
- , Tomas Jelinek
- & Michal Simicek
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Article
| Open Access
Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.
- Yandan Yang
- , Arnold Bolomsky
- & Ryan M. Young
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Article
| Open Access
CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
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Article
| Open Access
The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance.
- Leo Rasche
- , Carolina Schinke
- & Niels Weinhold
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Article
| Open Access
The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance
The myeloma cell surface proteome regulates plasma cell biology and delineates therapy targets. Here, the authors profile the myeloma surfaceome at baseline and in drug resistance, finding the potential target CCR10, and include a streamlined approach to primary sample analysis.
- Ian D. Ferguson
- , Bonell Patiño-Escobar
- & Arun P. Wiita
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Article
| Open Access
Blocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance
The bone tumour microenvironment plays an essential role in multiple myeloma (MM) development. Here, the authors show that bone collagen degradation provides glycine to support MM progression through glutathione and purine synthesis.
- Jiliang Xia
- , Jingyu Zhang
- & Wen Zhou
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Article
| Open Access
The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
- Josh N. Vo
- , Yi-Mi Wu
- & Arul M. Chinnaiyan
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Article
| Open Access
Osteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
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Article
| Open Access
Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes.
- Mark Bustoros
- , Shankara Anand
- & Irene M. Ghobrial
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Article
| Open Access
Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma
Acquired resistance to immunomodulatory drugs is common in multiple myeloma patients, but rarely attributed to genetic alterations. Here, proteomic, phosphoproteomic and RNA sequencing analysis in five paired pre-treatment and relapse samples reveals a CDK6-regulated protein resistance signature.
- Yuen Lam Dora Ng
- , Evelyn Ramberger
- & Jan Krönke
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Article
| Open Access
Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma
Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.
- Maximilian Merz
- , Almuth Maria Anni Merz
- & Jens Hillengass
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Article
| Open Access
Functional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
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Article
| Open Access
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics
Relapsed/refractory multiple myeloma (RRMM) is characterized by a remarkable heterogeneity and high drug resistance. Here, the authors analyse RRMM samples by single-cell RNA-sequencing, revealing molecular features associated with high-risk chromosomal 1q-gain and changes in the tumor microenvironment.
- Stephan M. Tirier
- , Jan-Philipp Mallm
- & Karsten Rippe
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Article
| Open Access
Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression
The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies.
- Danielle C. Croucher
- , Laura M. Richards
- & Suzanne Trudel
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Article
| Open Access
Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma
Despite extensive genetic heterogeneity, nearly half of all multiple myeloma (MM) cases are driven by cyclin D2 (CCND2) over-expression. Here the authors dissect the chromatin landscape of MM to provide insights into the transcriptional regulatory landscape driving MM and divergent transcriptomes corresponding to different MM genetic subtypes.
- Jaime Alvarez-Benayas
- , Nikolaos Trasanidis
- & Anastasios Karadimitris
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Article
| Open Access
Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma
Chromothripsis is associated with unfavourable outcomes in multiple myeloma (MM), but its detection usually requires whole genome sequencing. Here the authors develop an approach to detect chromothripsis in MM based on copy-number signatures that also works with whole exome sequencing data.
- Kylee H. Maclachlan
- , Even H. Rustad
- & Francesco Maura
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Article
| Open Access
Co-evolution of tumor and immune cells during progression of multiple myeloma
Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.
- Ruiyang Liu
- , Qingsong Gao
- & Li Ding
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Article
| Open Access
Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.
- Bénedith Oben
- , Guy Froyen
- & Francesco Maura
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Article
| Open Access
Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma
The mechanisms behind acquired resistance to the proteasome inhibitor bortezomib in multiple myeloma remain to be elucidated. Here, the authors show that the histone methyltransferase NSD2 stabilized SRC-3 protein levels, promotes its phase separation and alters H3K36me2 at certain gene promoters resulting in a transcriptional profile that favors resistance of myeloma cells to bortezomib.
- Jing Liu
- , Ying Xie
- & Zhiqiang Liu
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Article
| Open Access
Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma
Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.
- Mehmet Kemal Samur
- , Mariateresa Fulciniti
- & Nikhil C. Munshi
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Article
| Open Access
Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.
- Antonio Garcia-Gomez
- , Tianlu Li
- & Esteban Ballestar
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Article
| Open Access
Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma
The tumour microenvironment (TME) has a major role in chemoresistance in multiple myeloma. The authors show that a nanoparticle targeted to TME and loaded with bortezomib (BTZ) and Y27632 is more effective than free drugs, non-targeted and single-agent controls and reduces BTZ-related side effects.
- Cinzia Federico
- , Kinan Alhallak
- & Abdel Kareem Azab
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Article
| Open Access
Accelerated single cell seeding in relapsed multiple myeloma
In multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.
- Heather J. Landau
- , Venkata Yellapantula
- & Francesco Maura
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Article
| Open Access
Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant
Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
- Tarek H. Mouhieddine
- , Adam S. Sperling
- & Irene M. Ghobrial
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Article
| Open Access
Evolution and structure of clinically relevant gene fusions in multiple myeloma
Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.
- Steven M. Foltz
- , Qingsong Gao
- & Ravi Vij
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Article
| Open Access
Timing the initiation of multiple myeloma
The initial mutational processes and how these lead to progression in multiple myeloma (MM) are unclear. Here, the authors identify mutational signatures that occur over time in a large cohort of MM patients and suggest features that may help in early diagnosis.
- Even H. Rustad
- , Venkata Yellapantula
- & Francesco Maura
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Article
| Open Access
Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.
- Richa Bajpai
- , Aditi Sharma
- & Mala Shanmugam
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Article
| Open Access
CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide
CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes. Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells.
- Sabarinath V. Radhakrishnan
- , Tim Luetkens
- & Djordje Atanackovic
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Article
| Open Access
Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains
Chimeric antigen receptors (CAR) use antibody variable regions to activate anti-tumor immunity. Here the authors show that a mouse IgH/IgL variable region used in a clinical CAR induces host immune responses to possibly reduce therapy efficacy, but an IgH-only CAR T design achieves similar CAR T activity but is potentially less immunogenic.
- Norris Lam
- , Nathan D. Trinklein
- & James N. Kochenderfer
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Article
| Open Access
NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains
In multiple myeloma, a 4;14 translocation induces overexpression of histone methyltransferase NSD2, resulting in expansion of H3K36me2 and shrinkage of H3K27me3 domains. Here the authors find that CTCF, H3K27ac and gene expression changes cluster within a subset of insulated domains implicating 3D chromosome organization as a key factor in the NSD2-mediated phenotype.
- Priscillia Lhoumaud
- , Sana Badri
- & Jane A. Skok
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Article
| Open Access
Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
Multiple myeloma is a cancer of the bone marrow that can induce bone disease. Here, the authors profile the transcriptome of bone-lining cells and find a targetable role of bone morphogenetic protein (BMP) signalling in myeloma-induced bone-disease
- Sarah Gooding
- , Sam W. Z. Olechnowicz
- & Claire M. Edwards
Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial