Current overview and treatment of mantle cell lymphoma

Schieber, Michael; Gordon, Leo I.; Karmali, Reem

doi:10.12688/f1000research.14122.1

Cited by 38 publications

(48 citation statements)

References 50 publications

(54 reference statements)

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“…Collectively, these changes result in cell cycle dysregulation and give rise to profound genetic instability [2]. Despite being initially responsive to combination chemotherapy, relapsed patients have an overall survival of less than three years [3]. Therefore, it is essential to explore new treatment options targeting the numerous dysregulated pathways that are operable in MCL.…”

Section: Introductionmentioning

confidence: 99%

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

Lee

Sun

Webb

2020

Cells

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Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells. Therapeutic targeting of the S1P 1 receptor or knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in Natural Killer T (NKT) cell activation. NKT cells recognize glycolipid antigens presented on CD1d and can reduce MCL tumor burden in vivo. Lipidomic studies identified cardiolipin, which has been reported to bind to CD1d molecules, as being upregulated in SK1 knockdown cells. We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by NKT cell hybridomas. Furthermore, the ability of cardiolipin to activate NKT cells was dependent on the structure of its acyl chains. Collectively, these studies delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma.as ischemia reperfusion injury [10]. NKT cells are characterized by a semi-invariant T cell receptor (TCR) (Vα14Jα18 in mice and Vα24Jα18 in humans). Unlike conventional CD4 and CD8 T cells, NKT cells are activated by glycolipid antigens presented in the context of the non-classical, class I major histocompatibility complex (MHC)-like molecule, CD1d [11,12]. α-Galactosylceramide (α-GalCer) is a potent activator of NKT cells [13,14], and following treatment with α-GalCer, NKT cells produce cytokines, undergo clonal expansion, and subsequently activate other immune cells [15][16][17][18][19]. After activation, human NKT cells can exhibit strong anti-tumor activity against many tumors [20,21]. Several groups have conducted clinical trials evaluating the effectiveness of α-GalCer as a potential therapeutic immunomodulator of NKT cells that yielded modest results, potentially due to a reduction in NKT cell number and function in cancer patients [22][23][24][25][26][27].Sphingosine-1-phosphate (S1P) regulates proliferation, survival, and migration of mammalian cells through both extracellular receptor-mediated and intracellular mechanisms [28][29][30]. S1P is generated from sphingolipids, essential serum membrane lipids which are concentrated in lipid rafts. There are several enzymes in this pathway, which culminates in sphingosine kinase (SK) conversion of sphingosine into S1P. S1P is involved in malignant transformation, cancer cell proliferation, inflammation, vasculogenesis, lymphocyte trafficking, and resistance to apoptosis. There are two forms of sphingosine kinase: SK1 and SK2. Over-expression of SK1 has been reported to induce malignant transformation and tumor formation in 3T3 fibroblasts [31], while SK2 has been shown to promote acute lymphoblastic leukemia by increasing MYC expression [32]. In additio...

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Section: Introductionmentioning

confidence: 99%

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

Lee

Sun

Webb

2020

Cells

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“…1 Although MCL represents only ;6% of NHL lymphoma cases, it has one of the highest mortality rates of all lymphomas with only a 50% 5-year survival. 2 Given the high mortality rate and propensity for recurrence, understanding mutations found in MCL and disease development in B cells will open avenues for identifying new therapies. Recently, monoallelic mutations in the ubiquitin protein ligase E3 component n-recognin 5 (UBR5) were found in ;18% of patients with MCL.…”

Section: Introductionmentioning

confidence: 99%

UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells

Swenson

Gilbreath

Vahle

et al. 2020

Blood

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Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including mutations in the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5, with the majority of mutations within the HECT domain of the protein that can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B-cell maturation and activation, we generated a conditional mutant disrupting UBR5′s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and upregulation of proteins associated with messenger RNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B-cell maturation by stabilization of spliceosome components during B-cell development and suggests UBR5 mutations play a role in MCL transformation.

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“…Here we characterize MCL, a non-Hodgkin B-cell lymphoma that has very poor long-term survival (Schieber et al, 2018), and DHL, an extremely aggressive subtype of B-cell lymphoma that overexpresses both MYC and BCL-2 (Reagan and Davies, 2017), to define mechanisms that drive drug tolerance and resistance against ABT-199.…”

Section: Introductionmentioning

confidence: 99%

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

et al. 2019

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SUMMARY Drug-tolerant “persister” tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.

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Current overview and treatment of mantle cell lymphoma

Cited by 38 publications

References 50 publications

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

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