Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies

Jalali, Shahrzad; Ansell, Stephen M.

doi:10.3389/fcell.2021.692320

Cited by 4 publications

(3 citation statements)

References 72 publications

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“…Distinctive environmental factors, particularly the excess BM adiposity, may in uence absolute and relative cellular population distribution at the marrow microenvironment ( 5). This unbalanced microenvironment might support recruitment of malignant cells, promoting BM metastasis formation, and maintenance of a speci c immunosuppressive environment that supports tumor growth (5,21,22). As seen in HL, the BM is one of the common sites for metastasis (24).…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Matos,

Marinho-Dias,

Ramalheira

et al. 2023

Preprint

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Background Excessive adiposity, or obesity, has been associated with cancer promotion, including an increased risk for developing Hodgkin Lymphoma (HL). However, the association between obesity and survival in HL can be somewhat paradoxical and may indeed influence prognosis. Examining the bone marrow (BM) cytokine profile in HL patients could provide insights into the mechanisms underlying the altered association between excess adiposity and HL. The BM is an important site for hematopoiesis and can be influenced by various factors, including disease processes and systemic metabolic changes associated with obesity. Methods From our cohort, we analyzed interstitial marrow fluid (IMF) from BM aspirates of 16 HL patients at diagnosis and 11 control subjects. Participants were then matched by sex, age, and Body mass index (BMI) for inclusion in our discovery protein array analysis (n = 8 HL and n = 8 donors). We validated our findings in the total sample by measuring adipokine-related molecules using ELISA. Adiposity was measured through abdominal circumference measurement and BMI. Gene expression analysis was conducted through RT-qPCR. Activated signaling pathways were analyzed using HL cell line (L428 cells). Statistical analyses were performed using SPSS and GraphPad. Results The IMF of HL patients presented downregulation of interleukins (IL-1α/β, IL-6sR, IL-12), chemokines (CCL2, CCL3, CCL16), IGF-axis mediators (IGFBP-1, IGFBP-2, IGFBP-3, IGF-1sR), sTNFRII, TGFβ1, leptin, osteoprotegerin (OPG), and Fas compared to healthy donors and after controlling for adiposity status. Interestingly, HL overweight/obese subjects showed up-regulation of OPG and lymphotactin in IMF. The results were confirmed by quantification of cytokines, where we observed lower levels of insulin growth factor binding protein IGFBP-3 and higher levels of OPG levels in HL patients. The high-molecular weight (HMW) and total of adiponectin levels were high in HL BM. We further demonstrate that LEPR, TGFβ1, and IGFBP3 transcripts were upregulated in fractionated BMAd from HL compared to controls, while IFG2R was upregulated in SC. Finally, we observed a possible modulation of L428 cells through IGFBP-3 in an IGF-1-dependent manner, which could be reflected in the BM TME of HL disease. Conclusions Our data supports a role for the insulin axis in the BM microenvironment of obese HL patients, particularly through the regulation of insulin ligand-binding proteins.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Matos,

Marinho-Dias,

Ramalheira

et al. 2023

Preprint

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“…Thus, it is possible that part of the BM supportive stroma remains as a residual niche supporting treatment-resistant lymphoma B cells. These stromal cells might thus facilitate FL B cell reseeding as FL is still incurable and characterized by multiple relapses 3,53 . Deeper characterization of this niche is hence required to better understand how FL relapses, to prevent such events and ameliorate patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

Lymphoma B cells remodel bone marrow stromal cell organization and function to induce a supportive cancer-associated fibroblast network

Dessauge,

Brauge,

Léonard

et al. 2023

Preprint

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Bone marrow (BM) involvement is a common feature of lymphomas deriving from germinal-center B cells and is associated with a bad prognosis. In particular, follicular lymphoma (FL) infiltrates the BM in 70% of cases, in association with a remodeling of surrounding tumor microenvironment. Analysis ofin vitro-expanded FL mesenchymal stromal cells (MSCs) revealed an extensive alteration of BM stromal cell phenotypic, transcriptomic, and functional profiles. However, the mechanisms supporting the direct interplay between lymphoma B cells and their permissive stromal nichein situhave not been yet identified. In the current work, we identified in the BM milieu of FL patients a deregulation of soluble and extracellular matrix (ECM) components reflecting inflammation and ectopic differentiation into lymphoid-like stromal cells. We reproduced the same alterations in a murine model of lymphoma B-cell xenograft where a scRNAseq approach identified LepRposMSCs as specifically and progressively reprogramed by tumor B-cell invasion. Analysis of FL BM collected before and after treatment confirmed that BM niche was partly dependent on the continuous contact with tumor B cells. Altogether, this work shed new lights on the kinetic and mechanisms of BM stromal niche reshaping in B-cell lymphoma.

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“…Together, these results indicate that the heterogeneity of microenvironment cells lies far beyond our understanding and remains to be further functionally explored. The cellular components of TME in the bone marrow are very different from those in lymph nodes (reviewed in separate articles 108 , 109 ). FL subclones with different gene expression profiles are detected between bone marrow and lymph nodes 109 , 110 .…”

Section: Composition and Function Of Tme In Flmentioning

confidence: 99%

Advances in the multi-omics landscape of follicular lymphoma

Xu¹,

Zheng²,

Zhao³

2023

Int. J. Biol. Sci.

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Follicular lymphoma (FL) is the most common indolent lymphoma originating from germinal center B cells. FL represents a clinically and biologically heterogeneous disease. Most patients have favorable outcomes, but a subset of patients experiences early progression or transformation and has a poor prognosis. Abnormalities in FL cells and tumor microenvironment have been revealed using multi-omics techniques, including genomic, epigenomic, transcriptomic and proteomic analysis. Recurrent somatic gene aberrations mainly involve epigenetic modifiers, transcription factors, oncogenic pathways and microenvironment modulators. Single-cell transcriptomic analysis show marked inter- and intra-patient FL subclone heterogeneity. In addition, a comprehensive profile of microenvironmental components is provided, unveiling the crosstalk between tumor and microenvironment that induce FL progression and facilitate immune escape. Together, these studies provide insights into the mechanisms and biomarkers of high-risk FL populations, as well as the potential targeted and immunotherapy options. Future research should focus on integrating multi-omics aberrations to optimize therapeutic strategies in FL.

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Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies

Cited by 4 publications

References 72 publications

Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Lymphoma B cells remodel bone marrow stromal cell organization and function to induce a supportive cancer-associated fibroblast network

Advances in the multi-omics landscape of follicular lymphoma

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