The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy

Pavlasová, Gabriela Mladonická; Mráz, Marek

doi:10.3324/haematol.2019.243543

Cited by 237 publications

(211 citation statements)

References 121 publications

(187 reference statements)

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…CDK6 was hyper-hydroxymethylated in HPV(−) tumors at seven intronic regions, is targeted in the treatment of certain breast cancers [ 45 ] and recently showed response in the treatment of oral squamous cell carcinoma [ 46 ]. CD20, which is regulated by the epigenetic markers NFκB and SMAD2/3 [ 47 ], is targeted in chronic lymphocytic leukemia and follicular lymphoma [ 48 ]. The NFκB pathway and SMAD2/3 genes were identified as important 5hmC markers in our study, suggesting a potential use of B cell markers in the immunotherapy of HNSCC.…”

Section: Discussionmentioning

confidence: 99%

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers

Liu¹,

Medeiros²,

Fernandez³

et al. 2020

Clin Epigenet

View full text Add to dashboard Cite

Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied. Results We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines. Conclusion Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.

show abstract

Section: Discussionmentioning

confidence: 99%

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers

Liu¹,

Medeiros²,

Fernandez³

et al. 2020

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…BCR signaling propensity is also affected by levels of cell-surface molecules that act as docking sites for positive or negative BCR pathway regulators, which include molecules such as CD19, CD22, and CD32. Recently, we have shown that a notorious therapeutic target in B cell malignancies, CD20, is also a positive BCR signaling regulator ( 28 ). When CD20 is silenced, response to BCR stimulation is weaker, as underscored by the lower phosphorylation of BCR-associated kinases and impaired calcium flux ( 29 , 30 ).…”

Section: Bcr Signaling and Its Cross-talk With Other Pathwaysmentioning

confidence: 99%

“…Ibrutinib with immune modulator lenalidomide and rituximab is under investigation in DLBCL and MCL but has not been successful in CLL ( 178 – 181 ). A profoundly studied possibility for therapy is combining “BCR inhibitors” with widely-used anti-CD20 monoclonal antibodies ( 28 ). However, adding rituximab to ibrutinib did not bring any clinical benefit and this is likely due to ibrutinib downregulating CD20 levels and/or interfering with effector cell functions ( 28 , 30 , 182 , 183 ).…”

Section: Targeting Ibrutinib Resistancementioning

confidence: 99%

“…A profoundly studied possibility for therapy is combining “BCR inhibitors” with widely-used anti-CD20 monoclonal antibodies ( 28 ). However, adding rituximab to ibrutinib did not bring any clinical benefit and this is likely due to ibrutinib downregulating CD20 levels and/or interfering with effector cell functions ( 28 , 30 , 182 , 183 ). Furthermore, ibrutinib has been shown to negatively regulate anti-CD20 induced apoptosis in MCL cell lines ( 184 ).…”

Section: Targeting Ibrutinib Resistancementioning

confidence: 99%

See 1 more Smart Citation

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

show abstract

“…16 It is well known that several epigenetic and transcription factors regulate expression of the MS4A1 gene and of the CD20 antigen. 18 Interestingly, mutations of the NOTCH1 intracellular domain lead to accumulation of mutated NOTCH1 in the nucleus and may alter the fine epigenetic regulation of MS4A1 and CD20 expression through interactions with the RBPJ transcription factor that is involved in the NOTCH1 signaling pathway. 16,18 Overall, the biological relationship between NOTCH1 signaling, its deregulation by mutations and expression of CD20 requires further investigation, ideally in study designs aimed at comparing different type 1 and type 2 anti-CD20 mAb in order to understand not only the mechanisms of resistance, but also the strategies to overcome such refractoriness.…”

mentioning

confidence: 99%

A step ahead toward precision medicine for chronic lymphocytic leukemia

Patriarca

Gaïdano

2020

haematol

View full text Add to dashboard Cite

future. However, a note of caution is that many potential therapies have been shown to have in vivo efficacy in AML, but when tested clinically have had little or no effect on this disease. In conclusion, by targeting a number of different oncogenic pathways, in vitro and in vivo treatment with ARQ531 results in reduced AML cell viability, reduced tumor growth and improved survival of animals. The research by Soncini et al. suggests that a multi-targeted inhibitor such as ARQ531 is required to impair AML survival effectively; since this drug does not rely specifically on high expression of BTK or other tyrosine kinases it could be widely applicable to different subtypes of AML.

show abstract

The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy

Abstract: The DNA binding site in the MS4A1 promoter has not been defined. NICD: NOTCH1 intracellular domain.

Cited by 237 publications

References 121 publications

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

A step ahead toward precision medicine for chronic lymphocytic leukemia

Contact Info

Product

Resources

About