Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma

Zhang, Shaojun; Jiang, Changying; Han, Guangchun; Hao, Dapeng; Lian, Jiamei; Liu, Yang; Zhang, Rongjia; McIntosh, Joseph; Wang, Ruiping; Dang, Minghao; Dai, Enyu; Wang, Yuanxin; Santos, David M. Cordas dos; Badillo, Maria; Leeming, Angela; Chen, Zhihong; Hartig, Kimberly; Bigcal, John; Zhou, Jia; Kanagal‐Shamanna, Rashmi; Ok, Chi Young; Lee, Hun; Steiner, Raphaël; Zhang, Jianhua; Song, Xingzhi; Nair, Ranjit; Ahmed, Sairah; Rodriquez, Alma; Thirumurthi, Selvi; Jain, Preetesh; Wagner‐Bartak, Nicolaus A.; Hill, Holly A.; Nomie, Krystle; Flowers, Christopher R.; Futreal, Andrew; Wang, Linghua; Wang, Michael

doi:10.1038/s41467-021-22872-z

Cited by 42 publications

(57 citation statements)

References 73 publications

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“…To gain insight into this heterogeneity at single cell level, we performed single cell mRNA sequencing of the purified CD19 + fraction of diagnostic bone marrow aspirates from eight MCL patients. The inter-tumor heterogeneity was striking as previously reported in MCL 47 . However, in contrast to the subclonal involvement, as shown on unsorted mononuclear cells by two recent scRNA-seq studies 47 , 48 , the transcriptional profiles observed in this study were rather unremarkable with a homogeneous continuum of expression patterns observed for the malignant cells.…”

Section: Discussionsupporting

confidence: 82%

“…The inter-tumor heterogeneity was striking as previously reported in MCL 47 . However, in contrast to the subclonal involvement, as shown on unsorted mononuclear cells by two recent scRNA-seq studies 47 , 48 , the transcriptional profiles observed in this study were rather unremarkable with a homogeneous continuum of expression patterns observed for the malignant cells.…”

Section: Discussionsupporting

confidence: 82%

“…CD19 and CD5 expressions were not detected in all cells at the transcriptional level, as reported previously 48 , indicating a relatively low mRNA abundance or a poor correlation of the proteins and mRNA. Neither CCND1 nor SOX11 was expressed in all malignant B cells from MCL patients and not all SOX11 + cells expressed CCND1, as observed previously 47 . Collectively, this phenomenon may be explained by transcriptional bursting 49 – 51 or simply that the expression levels of the genes were below the detection limit or resolution of the scRNA-seq assay.…”

Section: Discussionsupporting

confidence: 79%

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Detailed characterization of the transcriptome of single B cells in mantle cell lymphoma suggesting a potential use for SOX4

Hansen

Cédile

et al. 2021

Sci Rep

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Mantle cell lymphoma (MCL) is a malignancy arising from naive B lymphocytes with common bone marrow (BM) involvement. Although t(11;14) is a primary event in MCL development, the highly diverse molecular etiology and causal genomic events are still being explored. We investigated the transcriptome of CD19+ BM cells from eight MCL patients at single-cell level. The transcriptomes revealed marked heterogeneity across patients, while general homogeneity and clonal continuity was observed within the patients with no clear evidence of subclonal involvement. All patients were SOX11+CCND1+CD20+. Despite monotypic surface immunoglobulin (Ig) κ or λ protein expression in MCL, 10.9% of the SOX11 + malignant cells expressed both light chain transcripts. The early lymphocyte transcription factor SOX4 was expressed in a fraction of SOX11 + cells in two patients and co-expressed with the precursor lymphoblastic marker, FAT1, in a blastoid case, suggesting a potential prognostic role. Additionally, SOX4 was found to identify non-malignant SOX11– pro-/pre-B cell populations. Altogether, the observed expression of markers such as SOX4, CD27, IgA and IgG in the SOX11+ MCL cells, may suggest that the malignant cells are not fixed in the differentiation state of naïve mature B cells, but instead the patients carry B lymphocytes of different differentiation stages.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 79%

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Detailed characterization of the transcriptome of single B cells in mantle cell lymphoma suggesting a potential use for SOX4

Hansen

Cédile

et al. 2021

Sci Rep

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“…In line with this, leukemia samples as well as lymphoma cells circulating in the peripheral blood were the subjects in hematology-focused projects of early days [ 26 , 27 ], with acute myeloid leukemia (AML) being the most frequently published oncohematological entity [ 28 ]. To date, SCS datasets have been generated for a wide range of blood cancers, including chronic myeloid leukemia [ 29 ], myeloproliferative neoplasms [ 30 , 31 ], myelodysplastic syndrome/acute myeloid leukemia [ 21 , 27 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], acute lymphoblastic leukemia (ALL) [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], chronic lymphocytic leukemia [ 59 , 60 , 61 ], mantle cell lymphoma [ 61 , 62 , 63 ], follicular lymphoma [ 61 , 64 , 65 , 66 ], diffuse large B-cell lymphoma [ 61 ], multiple myeloma [ 26 , 67 ], Hodgkin lymphoma […”

Section: Introductionmentioning

confidence: 99%

Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

Alpár

Egyed

Bödör

et al. 2021

Cancers

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Single-cell sequencing (SCS) provides high-resolution insight into the genomic, epigenomic, and transcriptomic landscape of oncohematological malignancies including pediatric leukemia, the most common type of childhood cancer. Besides broadening our biological understanding of cellular heterogeneity, sub-clonal architecture, and regulatory network of tumor cell populations, SCS can offer clinically relevant, detailed characterization of distinct compartments affected by leukemia and identify therapeutically exploitable vulnerabilities. In this review, we provide an overview of SCS studies focused on the high-resolution genomic and transcriptomic scrutiny of pediatric leukemia. Our aim is to investigate and summarize how different layers of single-cell omics approaches can expectedly support clinical decision making in the future. Although the clinical management of pediatric leukemia underwent a spectacular improvement during the past decades, resistant disease is a major cause of therapy failure. Currently, only a small proportion of childhood leukemia patients benefit from genomics-driven therapy, as 15–20% of them meet the indication criteria of on-label targeted agents, and their overall response rate falls in a relatively wide range (40–85%). The in-depth scrutiny of various cell populations influencing the development, progression, and treatment resistance of different disease subtypes can potentially uncover a wider range of driver mechanisms for innovative therapeutic interventions.

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“…advance for patients with refractory MCL. But despite these advances, drug resistance 15 and frequent relapses occur, and MCL remains incurable.…”

mentioning

confidence: 99%

Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Jain

Wang

2022

American J Hematol

Self Cite

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The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1-negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53, NSD2, KMT2D), methylation status, chromatin organization pattern, SOX-11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B-cell receptor signaling, nuclear factor kappa B (NF-kB), colony-stimulating factor (CSF)-1, the CD70-SOX-11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B-cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remain a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing. 1 | INTRODUCTION Mantle cell lymphoma (MCL) is an uncommon subtype of aggressive B cell non-Hodgkin's lymphoma (B-NHL). In 1982, Weisenburger et al. 1 first described 12 cases of malignant lymphoma with lymph node biopsies showing widened mantle zones around germinal centers in the secondary lymphoid follicles. The diagnosis of MCL 2 is now well characterized. MCL is no longer considered a single disease but is a mixed bag of various subcategories with a spectrum of molecular and clinical features. MCL patients have varied clinical presentations (generally symptomatic to an asymptomatic indolent clinical course).Advances in MCL research have significantly enhanced our understanding of pathogenesis, tumor microenvironment, 3 risk factor prognostication, 4 and molecular categories. 5 With the available treatment modalities (chemoimmunotherapy, 6 stem cell transplantation [SCT], 7 covalent and noncovalent BTK inhibitors, 8,9 bispecific antibodies, 10 an ROR1 drug conjugate, 11 and Bcl2 antagonists 12 ), the response rates and patient survival have improved. 13 The FDA approval of anti-CD19-chimeric antigen receptor therapy (CAR-T)-brexucabtagene autoleucel 14 -is a landmark

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Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma

Cited by 42 publications

References 73 publications

Detailed characterization of the transcriptome of single B cells in mantle cell lymphoma suggesting a potential use for SOX4

Detailed characterization of the transcriptome of single B cells in mantle cell lymphoma suggesting a potential use for SOX4

Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

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