Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a heterogeneous disease in Western and Chinese populations, and it is still not well characterized in Chinese patients. Based on a large cohort of newly diagnosed CLL/SLL patients from China, we investigated immunophenotypes, genetic abnormalities, and their correlations. Eighty-four percent of the CLL/SLL patients showed typical immunophenotypes with scores of 4 or 5 points in the Royal Marsden Hospital (RMH) scoring system (classic group), and the remaining 16% of patients were atypical with scores lower than 4 points (atypical group). Trisomy 12 and variants of TP53, NOTCH1, SF3B1, ATM, and MYD88 were the most recurrent genetic aberrations. Additionally, unsupervised genomic analysis based on molecular genetics revealed distinctive characteristics of MYD88 variants in CLL/SLL. By overlapping different correlation grouping analysis from genetics to immunophenotypes, the results showed MYD88 variants to be highly related to atypical CLL/SLL immunophenotypes. Furthermore, compared with mantle cell lymphoma (MCL), the genetic landscape showed potential value in clinical differential diagnosis of atypical CLL/SLL and MCL patients. These results reveal immunophenotypic and genetic features, and may provide insights into the tumorigenesis and clinical management of Chinese CLL/SLL patients.

UNASSIGNED: The immune landscape, prognostic model, and molecular variations of mantle cell lymphoma (MCL) remain unclear. Hence, an integrated bioinformatics analysis of MCL datasets is required for the development of immunotherapy and the optimization of targeted therapies.
UNASSIGNED: Data were obtained from the Gene Expression Omnibus (GEO) database (GSE32018, GSE45717 and GSE93291). The differentially expressed immune-related genes were selected, and the hub genes were screened by three machine learning algorithms, followed by enrichment and correlation analyses. Next, MCL molecular clusters based on the hub genes were identified by K-Means clustering, the probably approximately correct (PAC) algorithm, and principal component analysis (PCA). The landscape of immune cell infiltration and immune checkpoint molecules in distinct clusters was explored by single-sample gene-set enrichment analysis (ssGSEA) as well as the CIBERSORT and xCell algorithms. The prognostic genes and prognostic risk score model for MCL clusters were identified by least absolute shrinkage and selection operator (LASSO)-Cox analysis and cross-validation for lambda. Correlation analysis was performed to explore the correlation between the screened prognostic genes and immune cells or immune checkpoint molecules.
UNASSIGNED: Four immune-related hub genes (CD247, CD3E, CD4, and GATA3) were screened in MCL, mainly enriched in the T-cell receptor signaling pathway. Based on the hub genes, two MCL molecular clusters were recognized. The cluster 2 group had a significantly worse overall survival (OS), with down-regulated hub genes, and a variety of activated immune effector cells declined. The majority of immune checkpoint molecules had also decreased. An efficient prognostic model was established, including six prognostic genes (LGALS2, LAMP3, ICOS, FCAMR, IGFBP4, and C1QA) differentially expressed between two MCL clusters. Patients with a higher risk score in the prognostic model had a poor prognosis. Furthermore, most types of immune cells and a range of immune checkpoint molecules were positively correlated with the prognostic genes.
UNASSIGNED: Our study identified distinct molecular clusters based on the immune-related hub genes, and showed that the prognostic model affected the prognosis of MCL patients. These hub genes, modulated immune cells, and immune checkpoint molecules might be involved in oncogenesis and could be potential prognostic biomarkers in MCL.

UNASSIGNED: Bruton tyrosine kinase inhibitor (BTKi) resistance is an unsolved problem in the treatment of relapse/recurrence (R/R) mantle cell lymphoma (MCL). Although salvage therapy following ibrutinib resistance has been attempted in recent years, the survival of resistant patients was significantly reduced. Once ibrutinib-treated patients relapse, the 1-year survival rate is only 22%. Acquired drug resistance and primary drug resistance were found to relate closely to genetic mutations. The hub genes identification and clinical data analysis of patients resistant to BTKi based on the Chinese MCL gene mutation profile are worthy of exploration.
UNASSIGNED: Based on 28 MCL patients\' mutation data and clinical data, 6 hub genes were screened by a gene panel of 69 genes and univariate Cox prognostic analysis. Prognosis and responses to salvage therapy regimen were analyzed.
UNASSIGNED: Patients with BTKi had less favorable clinical features at baseline. Chimeric antigen receptor T-cell (CAR-T) therapy yielded the best response among salvage treatments. The 6 hub genes were screened by a gene panel of 69 genes (GP79) which might be a potential predictor for MCL patients with BTKi resistance.
UNASSIGNED: The clinical characteristics of BTKi resistance in MCL patients were summarized, and 6 hub genes were identified to provide ideas and suggestions for further research.

Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator\'s choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.
MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a noncovalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor. Clinical Trial Registration: NCT04662255 (ClinicalTrials.gov).

BACKGROUND: Mantle cell lymphoma (MCL) with co-expression of CD10 and BCL-6 was scarcely reported, and its biological features were largely remained unknown. Thus, this study aimed to describe the clinical and biological features, as well as outcome of MCL patients with co-expression of CD10 and BCL-6.
METHODS: A total of 104 cases of MCL who were admitted to our hospital between January 2011 and October 2018 were recruited. Those patients were diagnosed according to the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues, in compliance with the results of cytomorphology and immunohistochemical analysis. Patients were followed up through telephone interviews, medical records. Differences in age, gender, leukocyte count, lactate dehydrogenase (LDH) level, beta-2 microglobulin (β2-MG) level and results of immunohistochemistry were analyzed. Then the event-free survival (EFS) rate and overall survival (OS) rate were performed by the Kaplan-Meier method and log-rank test.
RESULTS: The results showed that, in total, 5 patients had superficial lymph node enlargement, 2 patients suffered from abdominal discomfort, and 1 patient\'s red blood cell (RBC) count was abnormal at the time of diagnosis. All patients were in stage IV, 75% had bone marrow involvement, and 75% and 100% of patients had elevated levels of LDH and β2-MG, respectively. Three classic genes and five variants were involved in the 8 patients. MCL patients with the co-expression of CD10 and BCL-6 had higher Ki-67 index, white blood cell (WBC) count, LDH level, and β2-MG level than those of without co-expression of CD10 and BCL-6 (P=0.025, 0.038, 0.015, and 0.021, respectively). Besides, MCL patients with CD10 and BCL-6 co-expression had shorter OS and EFS (χ2=6.401 and 5.975; P=0.011 and 0.015, respectively), indicating patients\' susceptibility to get complex karyotype and TP53 abnormality.
CONCLUSIONS: MCL patients with co-expression of CD10 and BCL-6 were more likely to have bone marrow involvement, higher Ki-67 index, increased WBC count, and elevated levels of LDH and β2-MG at the time of diagnosis, then might has complex cytogenetic and poor prognosis.

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma with a generally aggressive and heterogeneous clinical course. Chemokines are one of the complex components in the tumor microenvironment (TME), and they play a vital role in tumor progression and metastasis. There is no information about the monokine induced by gamma interferon (MIG)/CXC chemokine receptor 3 (CXCR3) axis in patients with MCL. In the present study, we discovered that CXCR3 was highly expressed in MCL tissues and some cell lines including Maver, Z138, and Jeko-1, and significantly associated with clinical factors reflecting high tumor burden in MCL patients. Moreover, elevated serum MIG at diagnosis showed a close relationship with advanced disease and poor prognosis in MCL patients. Additionally, the role of CXCR3 in promoting the proliferation and inhibiting the apoptosis of primary MCL cells and Jeko-1 cells was validated by in vitro experiments. Further research indicated that the MIG/CXCR3 axis mediated MCL cell migration to the TME through the PI3K/AKT signaling pathway. Therefore, the MIG/CXCR3 axis might be a potential target with fewer off-target side effects than other targets in MCL.

Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin\'s lymphoma (NHL), comprising about 6% of NHL cases. SOX11 is a member of the group C of Sry-related high-mobility group (HMG) box (Sox) transcription factors, which is ubiquitously expressed in approximate 90% MCL cases. However, the underlying mechanisms of the SOX11 expression aberration are not fully unveiled. In the present study, we firstly observed that miR-132-3p was dramatically down-regulated in CD19+ lymphocytes isolated from peripheral blood mononuclear cells (PBMCs) of MCL patients. Subsequently, we found miR-132-3p exhibited potentials in clinical application, indicated by its negative association with high-risk clinical features. In terms of function, ectopic miR-132-3p aggravated cell apoptosis and arrested cell cycle in G0/G1, and then inhibited cell proliferation in vitro and tumor growth in vivo. Also, we identified miR-132-3p\'s direct target, SOX11, in MCL cell lines, and loss-function of SOX11 blocked its inhibitory effect on cell proliferation in vitro. Collectively, our observations bring about a novel mechanism to explain the aberrant expression of SOX11 in MCL. Therefore, miR-132-3p may be a promising biomarker for the diagnosis of MCL.

OBJECTIVE: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5-negative pleomorphic variant MCL.
METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization.
RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1-IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases.

Mantle cell lymphoma (MCL) is a set of heterogeneous non-Hodgkin lymphoma characterized by involvement of lymph nodes, spleen, bone marrow and blood. Under conventional treatment, survival time is 4 to 5 years with short remission period and there is still no standard treatment for MCL. In general, a close observation period called \"watchful waiting\" is used in elderly patients with low-risk slow clinical progress. And intensive chemotherapy including high-dose of cytarabine ± autologous hematopoietic stem cell transplantation (auto-HSCT) is recommended for younger and fit patients. Allogenic stem cell transplantation (allo-SCT) and drugs targeting the cell metabolic pathway, such as bortezomib (NF-κB inhibitor) and lenalidomide (anti-angiogenesis drug), are considerable treatments for relapsed/refractory patients. Clinical trials and less intensive chemotherapy such as R-CHOP (rituximab with cyclophosphamide, hydroxydaunomycin, oncovin and prednisone) and R-bendamustine should be considered for elderly MCL patients who are at intermediate/high risk. Recent clinical trials with ibrutinib (Bruton\'s Tyrosine Kinase inhibitor) and temsirolimus (mTOR inhibitor) have shown excellent efficacies in the treatment of MCL. This review will introduce the present status and major therapeutic progress in the treatment of MCL over recent years in order to provide a cutting edge to look into promising clinical progress of MCL.

OBJECTIVE: To investigate the effects of CAL-101, particularly when combined with bortezomib (BTZ) on mantle cell lymphoma (MCL) cells, and to explore its relative mechanisms.
METHODS: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B (NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups.
RESULTS: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment.
CONCLUSIONS: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.