Mantle Cell Lymphoma Cases Research Articles

Brexucabtagene autoleucel therapy induces complete remission in a primary refractory blastoid mantle cell lymphoma with neurolymphomatosis

Brexucabtagene autoleucel therapy induces complete remission in a primary refractory blastoid mantle cell lymphoma with neurolymphomatosis

Mantle cell lymphoma may have a different clinical course in Mexican Mestizos: Real-world data from a single center.

The biology of some hematological diseases varies among different populations. No previous studies have evaluated the clinical behavior of mantle cell lymphoma (MCL) in México. This is a retrospective review of MCL cases seen in Mexico from January 2003 to June 2020. A total of 12 cases were identified. There were nine males and three females; median age was 56 years. Eight patients had a high MCL international prognostic index score, one was intermediate, and three were low. Five patients had circulating malignant monoclonal cells. Initial treatment included rituximab, cyclophosphamide, daunorubicin, vincristine, and prednisone (R-CHOP) and CHOP. Subsequent treatment included hematopoietic stem cell transplantation in five patients; two were given maintenance therapy. Splenectomy was done in four patients. Median overall survival (OS) for all the patients has not been reached and exceeds 162 mos: OS at 162 mos was 56%. Achieving a complete remission (CR) after the first treatment was a significant prognostic factor, with a median OS exceeding 141 mos in patients achieving CR, and 16 mos among those not achieving CR (p = 0.0006). Some of MCL patients in Mexico have an indolent clinical course, particularly patients who achieve a CR to initial treatment and who undergo splenectomy.

Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma.

We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the deregulation of WCP and promotes cell growth in MCL. In support of this hypothesis, we found that the expression of WIF1 was detectable in none of the 4 MCL cell lines, and in only 2 of 5 tumors (40%) examined. Using methylation-specific PCR, we found evidence of gene methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2′-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated with substantial downregulations of various proteins in WCP, such as β-catenin and pGSK-3β. In conclusion, our results support the concept that gene methylation/silencing of WIF1 is a frequent event in MCL, and this abnormality contributes to the aberrant activation of WCP. These results have provided further evidence that aberrant Wnt signaling is pathogenetically important in MCL and it may represent a potential therapeutic target.

Classical and molecular methods in differentiation of mantle cell lymphoma and small lymphocytic lymphoma in composite lymphoma: a case report

Composite lymphoma (CL) is a very rare phenomenon. To date, only few cases of composite mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been reported by Sun et al. (Cytometry B Clin Cytom 2018;94(1):148-50), Hoeller et al. (Hum Pathol 2013;44(1):110-21), and Papathomas et al. (Hum Pathol 2012;43(4):467-80). In the majority of CL cases, the clonality relationship was not examined or could not be proven. So far, there is no optimal treatment strategy for CL. However, it has been a commonly accepted rule that the more aggressive component should be treated first. Thus, it is of vital importance to precisely distinguish the components of CL and to determine the response of a particular component to treatment. This may be done by monitoring the molecular minimal residual disease (mMRD) as reported by Pott et al. (Blood 2010;115(16):3215-23) and Pott (Semin Hematol 2011;48(3):172-84). This report presents the possibility of determining clonality of each CL component by using flow cytometry in parallel with specific molecular markers. Molecular analysis was performed by quantitative real-time PCR (qPCR) using two markers: IGH rearrangement as reported by van Dongen et al. (Leukemia 2003;17(12):2257-317) and SOX11 expression by Hamborg et al. (Eur J Haematol 2012;89(5):385-94) and Szostakowska et al. (Med Oncol 2018;35(4):49). The SOX11 expression allowed us to distinguish MCL and SLL subclones in a 60-year-old male with multifocal MCL/SLL as this marker is not detected in SLL as reported by Swerdlow et al. (2001) and Mozos et al. (Haematologica 2009;94(11):1555-62). To our best knowledge, this is the first example of the use of mMRD to distinguish CL components.

Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma

Primary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index (P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P < 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P < 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% (P = 0.48) and OS of 57% vs 71% vs 69% (P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.

Mantle Cell Lymphoma: An Immunomorphologic Study with SOX11 from a Tertiary Care Cancer Centre in Southern India

Introduction: Mantle Cell Lymphoma (MCL) is a relatively rare Non-Hodgkin Lymphoma (NHL) of mature B cells forming 5-7% of NHL. SOX11 has emerged as a useful antibody in the diagnosis of MCL with prognostic significance. Aim: To evaluate the immunomorphologic features and significance of SOX11 expression in MCL at a tertiary care cancer institute. Materials and Methods: This was a descriptive study which was conducted at a tertiary care cancer centre in Southern India over a period of five years from January 2013 to December 2017. Seventy six cases of newly diagnosed MCL with paraffin blocks were included in the study. Immunohistochemistry (IHC) with a panel of antibodies including SOX11 was carried out on Formalin Fixed Paraffin Embedded (FFPE) sections. Morphologic, immunologic findings were analysed and correlated with clinical data and survival, using Chi-square and Independent sample t-test to compare data and Kaplan-Meir method with Log Rank test for survival analysis. Results: Mantle Cell Lymphoma (MCL) formed in 5.8% of NHL with a striking male predominance (M:F ratio, 4.4:1), with mean age of 58 years at presentation and females at a younger age. Nearly 80% of patients presented at an advanced stage. Cervical lymphadenopathy was the most common presenting feature, followed by involvement of the gastrointestinal tract. There were 59 cases of classic and 17 cases of blastoid and pleomorphic MCL, with diffuse pattern being the most common in 36 (47.4%) cases. In the present study, 64 (92.8%) cases expressed SOX11 and showed heterogeneous staining with high expression in 34 (53.1%) cases and low expression in 30 (46.9%) cases. Ki-67 proliferation of more than 30% was seen in 52 (68.4%) cases and 30% or less in 24 (31.6%) cases. None of these findings had statistically significant correlation with survival, though high Ki-67, high MCL International Prognostic Index (MIPI) and blastoid/pleomorphic cases had relatively worse Overall Survival (OS). Conclusion: MCL is a disease of the elderly and in the present study it affected females at a slightly younger age as compared to males. SOX11 expression was heterogeneous in neoplastic cells and was complementary to cyclin D1 for diagnosis of MCL however, the staining intensity had no effect on survival.

Need to Inspect the Total Gastrointestinal Tract of Patients With Malignant Lymphomas.

Malignant lymphoma (ML) cases with overlapping gastrointestinal (GI) lesions are often encountered. We aimed to elucidate the importance of examining the GI tract in patients with ML and assess the overlap rate. We analysed 190 patients diagnosed with GI MLs. We compared the overlap rates among the different histopathological types. Twenty-five (13.2%) patients had overlapping GI lesions in more than two segments. The overlap rates were 100% in mantle cell lymphomas (MCL), 27.6% in follicular lymphomas (FL), and 16.3% in diffuse large B-cell lymphomas (DLBCL). MCL, FL, and DLBCL cases showed significantly higher overlap rates than mucosa-associated lymphoid tissue lymphoma cases (p<0.01). About 64.0% of cases of ML with overlapping lesions involved the small intestine. In GI ML cases, it is ideal to examine the entire GI tract by esophagogastroduodenoscopy, colonoscopy, and capsule endoscopy and/or balloon-assisted endoscopy, especially in MCL, FL, and DLBCL.

A Rare Prostate Pathology: Mantle Cell Lymphoma: A Case Report and Literature Review

Primary or secondary lymphoma of the prostate is a rare condition. Mantle cell lymphoma (MCL) represent 4-9% of all lymphomas. Prostate involvement with MCL is very rare, with only 11 reported cases up to now. Here we present a case with lower urinary tract symptoms and prostate-specific antigen (PSA) elevation diagnosed with MCL of the prostate. Prostate biopsy was performed in a 70-year-old patient due to increased PSA. After the pathology result was reported as prostatic MCL, imaging studies and sampling of additional pathological specimens were performed for staging. An improvement was observed in the urinary system complaints of the patient who started chemotherapy regimen. While prostatectomy was performed in some of the prostatic MCL cases reported previously, in some, no additional treatment was required after chemotherapy. Our case is the only prostatic MCL case with elevated PSA levels, but did not receive the diagnosis of prostate cancer. Physicians should keep in mind that, prostatic MCL can present with nonspecific symptoms. Staging should be performed in patients whose histopathologic diagnosis is lymphoma of the prostate so as to determine appropriate treatment options.

Using patient-specific bolus for pencil beam scanning proton treatment of periorbital disease.

PurposeA unique mantle cell lymphoma case with bilateral periorbital disease unresponsive to chemotherapy and with dosimetry not conducive to electron therapy was treated with pencil beam scanning (PBS) proton therapy. This patient presented treatment planning challenges due to the thin target, immediately adjacent organs at risk (OAR), and nonconformal orbital surface anatomy. Therefore, we developed a patient‐specific bolus and hypothesized that it would provide superior setup robustness, dose uniformity and dose conformity.Materials/MethodsA blue‐wax patient‐specific bolus was generated from the patient's face contour to conform to his face and eliminate air gaps. A relative stopping power ratio (RSP) of 0.972 was measured for the blue‐wax, and the HUs were overridden accordingly in the treatment planning system (TPS). Orthogonal kV images were used for bony alignment and then to ensure positioning of the bolus through fiducial markers attached to the bolus and their contours in TPS. Daily CBCT was used to confirm the position of the bolus in relation to the patient's surface. Dosimetric characteristics were compared between (a) nonbolus, (b) conventional gel bolus and (c) patient‐specific bolus plans. An in‐house developed workflow for assessment of daily treatment dose based on CBCT images was used to evaluate inter‐fraction dose accumulation.ResultsThe patient was treated to 24 cobalt gray equivalent (CGE) in 2 CGE daily fractions to the bilateral periorbital skin, constraining at least 50% of each lacrimal gland to under 20 Gy. The bolus increased proton beam range by adding 2–3 energy layers of different fields to help achieve better dose uniformity and adequate dose coverage. In contrast to the plan with conventional gel bolus, dose uniformity was significantly improved with patient‐specific bolus. The global maximum dose was reduced by 7% (from 116% to 109%). The max and mean doses were reduced by 6.0% and 7.7%, respectively, for bilateral retinas, and 3.0% and 13.9% for bilateral lacrimal glands. The max dose of the lens was reduced by 2.1%. The rigid shape, along with lightweight, and smooth fit to the patient face was well tolerated and reported as “very comfortable” by the patient. The daily position accuracy of the bolus was within 1 mm based on IGRT marker alignment. The daily dose accumulation indicates that the target coverage and OAR doses were highly consistent with the planning intention.ConclusionOur patient‐specific blue‐wax bolus significantly increased dose uniformity, reduced OAR doses, and maintained consistent setup accuracy compared to conventional bolus. Quality PBS proton treatment for periorbital tumors and similar challenging thin and shallow targets can be achieved using such patient‐specific bolus with robustness on both setup and dosimetry.

Frequency of MYD88 L256P mutation and its correlation with clinico-hematological profile in mature B-cell neoplasm

Objective/backgroundB-cell neoplasms are clonal tumors of B cells at various stages of maturation, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma (CLL), Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and hairy cell leukemia (HCL). In this study, we analyzed the frequency of MYD88 L265P mutation and its correlation with clinico-hematological profile in mature B-cell neoplasms. MethodsA total of 110 consecutive cases of B-cell neoplasms showing peripheral blood and/or bone marrow infiltration were included. MYD88 L265P mutation was detected by polymerase chain reaction amplification of exon 5 of MYD88 gene, followed by restriction fragment length polymorphism analysis. ResultsAmong the 110 cases, the major group was of CLL (54.5%, n = 60), followed by HCL. Other cases included MCL, LPL, DLBCL, SMZL, NMZL, FL, and BL. MYD88 L265P mutation was seen in 21 (19.1%) cases of B-cell neoplasm, whereas 89 (80.9%) cases were negative for MYD88 L265P mutation. It was most commonly seen in LPL/WM cases followed by HCL, SMZL, CLL, and MCL cases. No case of DLBCL, FL, and BL showed MYD88 L265P mutation. Statistically significant difference was seen for hemoglobin level in CLL cases, with MYD88 L265P mutated cases showing higher mean hemoglobin levels than MYD88 wild-type cases (p = .001). For other parameters, no statistically significant difference was noted between mutated and unmutated cases. ConclusionMYD88 L265P mutation is seen in various B-cell neoplasms; it is most commonly seen in LPL/WM cases but not specific for it.

CRISPR-Cas9 Knock out of CD5 Enhances the Anti-Tumor Activity of Chimeric Antigen Receptor T Cells

CRISPR-Cas9 Knock out of CD5 Enhances the Anti-Tumor Activity of Chimeric Antigen Receptor T Cells

Expression of CD180 in common B cell neoplasms using immunohistochemistry

Diagnosis of low-grade B cell lymphoma can be challenging especially on limited cytological and histological samples, CD180 is Toll-like receptor that was found to be of value in the diagnosis of marginal zone lymphoma using flow cytometry. In this pilot study, we examine the expression of CD180, using an immunohistochemical method, on a number of common B cell lymphoproliferative neoplasms. Immunohistochemical staining for sixty-seven cases of five B cell neoplasms, specifically, marginal zone lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma was performed on archived, paraffin-embedded, formalin-fixed tissue. CD180 expression is preserved in all cases of marginal zone lymphoma, sixteen out of 17 cases of follicular lymphoma cases, and none of the diffuse large B cell lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma cases. One in 12 cases of mantle cell lymphoma shows weak and focal staining. Using CD180 immunohistochemical stain can be valuable and offer some help in the diagnosis of B cell neoplasms, especially on small tissue samples.

ROLE AND RELEVANCE OF THE EUROFLOW ANTIBODY PANEL IN IMMUNOPHENOTYPING OF CHRONIC LYMPHOPROLIFERATIVE DISORDERS

Detection of phenotypically aberrant and clonal mature lymphocytes is the diagnostic hallmark of chronic lymphoproliferative disorders (CLPD). B-CLPD is the commonest of all the CLPD. In this study we evaluated the role of CD200 and CD43 new markers that have been introduced in the Euroflow panel in the separation between chronic lymphocytic leukemia (CLL) and all other mature B cell malignancies .These markers were also correlated with the markers used in the Matutes score like FMC7 and Surface membrane Immunoglobulin. Patient samples between October 2017-February 2018, peripheral blood or bone marrow aspirates of patients with suspected B-cell lymphoproliferative disorders were subjected to evaluation by flow cytometry. After washing, samples were stained by antibodies targeting the antigens CD45, CD19, CD5, CD10, CD20, CD23, CD43, CD79b, CD200, FMC7, CD25,CD103 ,CD11c ,sIgM, kappa and lambda . Immunophenotyping was performed using a BD FACS Canto flow cytometer. There were a total of 108 cases of B CLPD that were analysed by flow cytometry . Mean age (SD ) was 65 years. There were 68 males and 40 female patients . There were 71 cases of typical CLL , 7 cases of atypical CLL , 3 cases of Mantle cell lymphoma (MCL) , 5 cases of Follicular lymphoma ( FCL ) , 8 cases of Splenic lymphoma with villous lymphocytes (SLVL) , 6 cases of Hairy cell leukemia ( HCL) , 6 cases of unclassifiable B-NHL and 2 cases of lymphoplasmacytic lymphoma. All our cases of typical CLL showed bright expression of CD200 .It was also brightly expressed in all our atypical cases of CLL . CD43 was brightly positive in all our cases of typical CLL . The expression of this marker along with CD200 negativity was helpful in diagnosing of MCL.There were diagnostic difficulties in differentiating atypical CLL from B-NHL unclassifiable. The lack or dim expression FMC7 expression in all these cases along with absent or dim expression of sIgM were informative. Their use along with the panel by Euroflow is suggested to provide an accurate diagnosis.

Secondary Postpartum Haemorrhage: A Rare Presentation of Secondary Uterine Mantle Cell Lymphoma

Postpartum haemorrhage (PPH) is rarely the initial presentation of a disseminated non-Hodgkin lymphoma (NHL). Herein, we describe the very first case of a uterine mantle cell lymphoma (MCL) presenting with PPH. A 30-year-old P1L1 female patient presented with secondary PPH following an emergency caesarean section. Ultrasonogram revealed a hypo-echoic mass in the uterine cavity, histopathological examination of which revealed MCL. Metastatic evaluation of the patient showed a widespread disease with skeletal and lymph node involvement. She was staged Ann Arbor IV NHL with International Prognostic Index (IPI) of 2/5. Despite chemoradiation, she succumbed to leptomeningeal spread and expired 5 months from diagnosis. The involvement of female genital organs by malignant lymphomas is a rare but possible scenario with perilous outcomes. The unusual clinical presentations necessitate a high degree of suspicion with prompt pathological confirmation and individualised therapy.

Relationship of Expression of Circ_cgga162 with the Prognosis of Patients with Mantle Cell Lymphoma

To investigate the expression of Circ_cgga162 in serum of mantle cell lymphoma (MCL) patients and analyze its potential as a prognostic biomarker. The expression of Circ_cgga162 in 86 cases of mantle cell lymphoma and 50 cases of lymph node reactive hyperplasia (RH) were detected by real-time quantitative polymerase chain reaction (qRT-PCR). The relationship between the expression of Circ_cgga162 and clinicopathological features was analyzed by univariate analysis. The relationship of Circ_cgga162 expression with progression-free survival time and overall survival time was analyzed by Kaplan-Meier. The relationship between expression of Circ_cgga162 and prognosis of patients was analyzed by univariate and multivariate analysis. The expression level of Circ_cgga162 in MCL patients was significantly higher than that in control (RH) group (P＜0.01). The expression of Circ_cgga162 not correlated with age, gender, B symptoms and LDH (all P＞0.05), but correlated with the expression of MCL International Prognostic Index (IPI), Ann Arbor stage, bone marrow infiltration and Ki67 (all P＜0.05). In addition, Kaplan-Meier analysis showed that the progression-free survival time and overall survival time of the MCL patients with high expression of Circ_cgga162 were significantly shorter than those of the MCL patients with low expression (P＜0.01). Univariate analysis showed that Ann Arbor stage, Circ_cgga162 expression, MIPI, bone marrow infiltration and Ki67 were the prognostic factors for MCL patients (all P＜0.05). Multivariate Cox regression analysis showed that Ann Arbor stage, Circ_cgga162 expression and MIPI were independent factors affecting the prognosis of MCL patients (all P＜0.05). Circ_cgga162 is highly expressed in serum of patients MCL, which relates with the prognosis of MCL patients. Circ_cgga162 can be used as a potential prognostic marker and therapeutic target for MCL patients.

Mantle cell lymphoma: pathologic and immunophenotyping study of 50 cases and correlation with survival—a single institute experience

Mantle cell lymphoma (MCL) is a relatively rare lymphoma subtype. Almost all cases show common genetic abnormality t(11;14), resulting in overexpression of cyclin D1 protein. The clinical course is usually aggressive, and the disease is mainly considered incurable but obvious clinical heterogeneity exists. Most patients experience a rapidly progressive course, and some go through an indolent course of disease. So new strategies are needed for risk stratification and may allow for a more personalized approach in the future. We retrospectively studied 50 cases of MCL which were diagnosed at a single center over about 5 years to determine clinicopathologic and immunophenotyping findings. This study focuses on (1) age, gender, and location of tumor at presentation; (2) some challenges in the diagnostic criteria; (3) cytomorphology, histomorphology, immunophenotyping, and proliferation rate; and (4) overall survival and finally relationship with demographic and pathologic findings which shows no association between survival of patients and gender, cytomorphology, histology, and location of tumor while increased mitotic activity and age are prognostically important factors. Cyclin D1 immunostaining is strictly recommended in all low-grade B cell lymphoma due to absence of CD5 expression on 20% of confirmed MCL and also on all high-grade B cell lymphoma for avoiding overlook of blastic variant of MCL.

Mantle cell lymphoma: initial report from the North American Mantle Cell Lymphoma Consortium.

8035 Background: The goal of the North American Mantle Cell Lymphoma (MCL) Project is to evaluate the clinical, biological, and genomic markers that affect the outcome of patients with MCL. Methods: We have retrospectively studied the clinical and pathological features of 307/421 patients diagnosed with MCL between January 2000 to December 2012 from 23 institutions across North American. Results: The male to female ratio of MCL patients was 3.5:1, with a median age of 66 years (range: 24-106 years). Approximately 29% of patients (78/269) presented with B symptoms and 257 (257/307, 83.7%) patients had extranodal involvement at diagnosis. Median follow-up was 7.1 years (range, 0.03 to 16.6 years) with the five-year PFS and OS at 27.8%, and 54.4%, respectively. Univariate analysis revealed that the following factors were significantly associated with both inferior OS and PFS ( p&lt; 0.05): older age (≥60 years), presence of B symptoms, advanced Ann Arbor stage, elevated LDH, low platelets (≤100K/ml), blastoid/pleomorphic cytology, Ki67 proliferation ≥30%, circulating tumor cells, no transplantation (vs. transplantation), and allogeneic (vs. autologous) stem cell transplantation. In addition, large tumor size (maximal diameter &gt; 3cm), high WBC ( &gt; 10×103/ml), CD5 or CD23 positivity, and a complex karyotype were associated with inferior OS ( p&lt; 0.05). Multivariate Cox regression analysis showed age (≥ 60y; p= 0.0028, HR = 2.44, 95% CI: 1.36-4.38) and high LDH ( p= 0.0062, HR = 2.19, 95% CI: 1.25-3.84) were the two factors predicting the clinical outcome. MIPI-c, a commonly used prognostic scoring system which includes Ki67, stratified the 100 MCL cases into four group with distinct clinical outcomes ( p&lt; 0.001). Using readily-available clinical and pathological variables, we developed a simple and robust scoring system, MIPI-P (pathology), which consisted of age (≥60 years), LDH (high), Ki67 index (≥30%), Ann Arbor stage (III/IV), and cytological type (blastoid/pleomorphic), each contributing one point. The MIPI-P system stratified 104 MCL cases into three distinct groups ( p&lt; 0.001). Median survival for the different groups were: low grade (0-1 points): 11.8 years; intermediate grade (2-3 points): 4.9 years; and high grade (4-5 points): 1.6 years. We further validated this system in an independent cohort of 33 MCL cases and confirmed that the modified MIPI-P provided robust prognostic predication ( p= 0.014). Conclusions: The clinical and biologic characteristics of MCL can provide information assisting with the prognosis of patients with MCL.

Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study.

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.

MiR-132-3p serves as a tumor suppressor in mantle cell lymphoma via directly targeting SOX11.

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.

Stabilization of β-catenin upon B-cell receptor signaling promotes NF-kB target genes transcription in mantle cell lymphoma.

B-cell receptor (BCR) signaling pathways and interactions with the tumor microenvironment account for mantle cell lymphoma (MCL) cells survival in lymphoid organs. In several MCL cases, the WNT/β-catenin canonical pathway is activated and β-catenin accumulates into the nucleus. As both BCR and β-catenin are important mediators of cell survival and interaction with the microenvironment, we investigated the crosstalk between BCR and WNT/β-catenin signaling and analyzed their impact on cellular homeostasis as well as their targeting by specific inhibitors. β-catenin was detected in all leukemic MCL samples and its level of expression rapidly increased upon BCR stimulation. This stabilization was hampered by the BCR-pathway inhibitor Ibrutinib, supporting β-catenin as an effector of the BCR signaling. In parallel, MCL cells as compared with normal B cells expressed elevated levels of WNT16, a NF-κB target gene. Its expression increased further upon BCR stimulation to participate to the stabilization of β-catenin. Upon BCR stimulation, β-catenin translocated into the nucleus but did not induce a Wnt-like transcriptional response, i.e., TCF/LEF dependent. β-catenin rather participated to the regulation of NF-κB transcriptional targets, such as IL6, IL8, and IL1. Oligo pull down and chromatin immunoprecipitation experiments demonstrated that β-catenin is part of a protein complex that binds the NF-κB DNA consensus sequence, strengthening the idea of an association between the two proteins. An inhibitor targeting β-catenin transcriptional interactions hindered both NF-κB DNA recruitment and induced primary MCL cells apoptosis. Thus, β-catenin likely represents another player through which BCR signaling impacts on MCL cell survival.