Development of a Blastoid Variant, Mantle Cell Lymphoma Model in Transgenic Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 419-419
Author(s):  
Richard J. Ford ◽  
Yen-Chiu Lin-Lee ◽  
Long Shen ◽  
Connie Xu ◽  
Chongjie Zhang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
B Lymphocytes ◽  
Cell Lymphoma ◽  
Lymphoid Cells ◽  
Mantle Cell ◽  
B Lymphoid ◽  
Hodgkin's Lymphomas

Abstract Mantle Cell Lymphoma (MCL) is a poorly understood, aggressive histotype of B-cell non-Hodgkin’s Lymphomas (NHL-B) that remains the most therapeutically resistant of the NHL-B. Little is known regarding why MCL is so clinically aggressive and therapeutically refractory. Blastoid variant MCL (MCL-BV) is an even more aggressive form of MCL that appears to be increasing in incidence in the US. It may represent progression from classic MCL, often with leukemic involvement and complex lymphoma karyotypes. Interleukin 14 (IL-14) is cytokine that was identified and cloned from a Burkitt lymphoma (BL) cell line that acts as a growth factor for normal B-lymphocytes. The expression of IL-14a protein and mRNA levels are elevated at lease fifty-fold in B-cell non-Hodgkin’s Lymphomas (NHL-B), including mantle cell lymphoma (MCL), in contrast to very low levels of IL-14a in quiescent (Go) B cells by both western and northern blot analysis. To evaluate the role of IL-14 in vivo, we have generated transgenic mice expressing IL-14 with pEuSR. The IL-14 TG mice generally live a normal life span, however when autopsies are performed at 18 months of age, splenomegaly is noted, and 50% have evidence of B cell lymphoma. This lymphoma is CD5+, CD19+, sIgM+, CD21− and contains a monoclonal population of B-lymphocytes with rearranged immunoglobulin genes. Morphologically the lymphoma arising in IL-14 transgenic mice resembles the centroblastic/Immunoblastic histotype of DLBCL. Because of the frequent involvement of c-myc in various B cell malignancies, we crossed Eμ-myc (c-myc TG) mice with the IL-14 TG mice. By 3 months of age, 100% of the double transgenic (DTG) mice develop an aggressive B cell malignancy that is characterized by extensive lymphadenopathy and splenomegaly with intermediate to large atypical lymphoid cells, strongly resembling MCL-BV morphologically. This tumor, like that derived from the IL-14 TG mice, is CD5+, CD19+, sIgM+, CD21−. It is also CD23− and over-expresses Cyclin D1 in monoclonal B lymphoid cells with re-arranged IgH immunoglobulin genes, mimicking the MCL phenotype. At the time of autopsy, tumor infiltration of DTG mice is generally found in all organs evaluated, including peripheral blood, lymph nodes, spleen, liver, bone marrow, thymus and kidneys, consistent with the usual findings in MCL-BV. No tumors are observed in IL-14α TG or c-myc TG mice autopsied at this age. This MCL-BV model allows for the molecular and genotypic characterization of the murine B lymphoid cell compartment from birth to lymphoma development (3 mos.), including histogenesis and functional determination of the growth and survival characteristics of these tumors in DTG bone marrow and peripheral B cell populations. Preliminary comparative in vitro and in vivo (SCID Xeno-transplants) studies in DTG/MCL-BV lymphomas have shown additional molecular similarities to the pathophysiology (e.g constitutive NF-kB activation) of MCL-BV cell lines and patient samples, that should provide insights for future potential therapeutic approaches to MCL.

Combination Anti-CD74 (Milatuzumab) and CD20 (Rituximab) Monoclonal Antibody Therapy Has in Vitro and in Vivo Activity in Mantle Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 886-886 ◽  
Author(s):  
Lapo Alinari ◽  
Erin Hertlein ◽  
David M. Goldenberg ◽  
Rosa Lapalombella ◽  
Fengting Yan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Combination Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Preclinical Model ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an incurable B-cell malignancy and patients with this disease have limited therapeutic options. Despite the success of Rituximab in treatment of B-cell malignancies, its use as a single agent or in combination with chemotherapy in MCL has demonstrated modest activity; thus, novel strategies are needed. CD74 is an integral membrane protein expressed on malignant B cells and implicated in promoting survival and growth, making it an attractive therapeutic target. The humanized anti-CD74 monoclonal antibody (mAb), Milatuzumab, (Immunomedics) has shown promising preclinical activity against several human B-cell lymphoma cell lines, but has not been studied in MCL. Since Rituximab and Milatuzumab target distinct antigens lacking known association, we explored a combination strategy with these mAbs in MCL cell lines, patient samples, and in a preclinical model of MCL. Flow cytometric analysis shows that the MCL cell lines Mino and JeKo, and MCL patient tumor cells, express abundant surface CD74 compared to the CD74-negative cell line, Jurkat. Incubation of Mino and JeKo cells with immobilized (goat anti-human IgG) Milatuzumab (5 μg/ml) resulted in mitochondrial depolarization and significant induction of apoptosis determined by Annexin V/PI and flow cytometry (apoptosis at 8hr=38.3±0.85% and 25.4±2.6%; 24hr=73.6±3.47% and 36±3.57%; 48hr=84.9±3.91% and 50.4±4.17%, respectively, compared to Trastuzumab (control). Expression of surviving cells from anti-CD74-treated MCL cells consistently demonstrated marked induction of surface CD74 (MFI 762) compared to control (MFI 6.1). Incubation with immobilized Rituximab (10 μg/ml) resulted in 39.5±2.5% and 37.1±8.35% apoptotic events at 8hr, 58.8±3.14%, 41.2±8.27% at 24hr, and 40.1±1.3% and 45.6±3.25% at 48hr, respectively. Combination treatment of Mino and JeKo cells with Milatuzumab and Rituximab led to significant enhancement in cell death, with 77.6±3.95% and 79.6±2.62% apoptosis at 8hr in Jeko and Mino cells (P=0.0008 and P=0.00004 vs. Milatuzumab alone; P=0.00015 and P=0.001 vs. Rituximab alone); 90.4±3.53% and 76.6±4.3% at 24hr, respectively (P=0.0042 and P=0.0002 vs. Milatuzumab, P=0.0003 and P=0.0027 vs. Rituximab alone); 92.8±0.77% and 85.6±2.62% at 48hr, respectively (P= 0.026 and P=0.0002 vs. Milatuzumab alone, P=0.0000005 and P=0.00008 compared to Rituximab alone, respectively). To examine the in vivo activity of Rituximab and Milatuzumab, a preclinical model of human MCL using the SCID (cb17 scid/scid) mouse depleted of NK cells with TMβ1 mAb (anti-murine IL2Rb) was used. In this model, intravenous injection of 40×106 JeKo cells results in disseminated MCL 3–4 weeks after engraftment. The primary end-point was survival, defined as the time to develop cachexia/wasting syndrome or hind limb paralysis. Mice were treated starting at day 17 postengraftment with intraperitoneal Trastuzumab mAb control (300 μg qod), Milatuzumab (300 μg qod), Rituximab (300 μg qod), or a combination of Milatuzumab and Rituximab. The mean survival for the combination-treated group was 55 days (95%CI:41, upper limit not reached as study was terminated at day 70), compared to 33 days for Trastuzumab-treated mice (95% CI:31,34), 35.5 days for the Milatuzumab-treated mice (95% CI:33,37), and 45 days for the Rituximab-treated mice (95%CI:30,46). The combination treatment prolonged survival of this group compared to Trastuzumab control (P=0.001), Milatuzumab (P=0.0006) and Rituximab (P=0.098). No overt toxicity from Milatuzumab or the combination regimen was noted. A confirmatory study with a larger group of mice and detailed mechanistic studies are now underway. These preliminary results provide justification for further evaluation of Milatuzumab and Rituximab in combination in MCL.

scholarly journals Identification on Mantle Cell Lymphoma Using CD20 and CD5 Coupled Upconversion Fluorescent Nanoprobes

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Mingkai Zhang ◽  
Yang Gao ◽  
Jialiang Wang ◽  
Zhanbo Liu ◽  
Zaishun Jin ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Fluorescence Imaging ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Upconversion Fluorescence ◽  
Mantle Cell

In order to determine a particular tumor cell via nanomaterials, we introduce the preparation of CD20 and CD5 coupled nanoprobes (denoted as CD20 and CD5 nanoprobes for convenience) and an application in identification of mantle cell lymphoma (MCL) from B-cell lymphoma. In this work, CD20 and CD5 nanoprobes were prepared by selectively oxidizing the carbon-carbon double bonds of oleate ligands on the surfaces of NaYF4:Yb3+,Tm3+ and NaYF4:Yb3+,Er3+ nanoparticles and, respectively, coupling carboxyl groups on the particles’ surfaces with CD20 and CD5 monoclonal antibodies through EDC/NHS crosslinking agents. After in situ hybridized Jeko-1 cells and Raji cells as a reference with CD20 and CD5 nanoprobes, in vitro double-color upconversion fluorescence imaging of Jeko-1 cells was demonstrated through visualization of blue and green fluorescence under a 980 nm laser excitation. Moreover, in vivo upconversion fluorescence imaging of the transplanted cancer model was also measured. These experimental results indicate that Jeko-1 cells have been specifically labeled by CD20 and CD5 nanoprobes. It is therefore concluded that CD20 and CD5 nanoprobes could be used to specially differentiate mantle cell lymphoma (MCL) from B-cell lymphoma.

CNS involvement in mantle-cell lymphoma.

1996 ◽  
Vol 14 (3) ◽  
pp. 941-944 ◽  
Author(s):  
E Montserrat ◽  
F Bosch ◽  
A López-Guillermo ◽  
F Graus ◽  
M J Terol ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Lymphoid Cells ◽  
University Hospital ◽  
Cns Involvement ◽  
Resistant Disease ◽  
Mantle Cell ◽  
High Incidence ◽  
Hodgkin's Lymphomas ◽  
Lymphoma Type

PURPOSE In non-Hodgkin's lymphomas, CNS involvement is highly dependent on the histology of the lymphoma. Mantle-cell lymphoma (MCL) is a lymphoma type with distinctive histologic, biologic, and clinical features in which CNS involvement has only been rarely described. The purpose of this report is to describe the incidence, clinical characteristics, and outcome of CNS infiltration in patients with MCL seen at a single institution. PATIENTS AND METHODS Twenty-two patients with MCL, who account for 6% of all patients with nodal lymphomas diagnosed and monitored at a university hospital from 1987 to 1994, were studied. Analysis of the incidence of CNS involvement by the disease was performed. RESULTS Five of 22 patients (22%; exact 95% confidence interval [CI], 7.8% to 45.4%) with MCL developed CNS involvement at a median of 18 months (range, 6 to 59) from diagnosis. All of these patients presented with poor MCL histologic subtypes and advanced disease. When the CNS infiltration became apparent, all of the patients displayed neurologic signs and had lymphoid cells consistent with the diagnosis of MCL in the CSF. In most of the cases, CNS infiltration was part of resistant disease or generalized relapse and had an ominous significance. CONCLUSION The incidence of CNS involvement in MCL might be higher than previously recognized. The frequency of CNS infiltration in MCL deserves to be investigated in other series and, if a high incidence is confirmed, the risk factors, mechanisms, and clinical implications of such a complication should be further studied.

JunB inhibits proliferation and transformation in B-lymphoid cells

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4159-4165 ◽  
Author(s):  
Agnieszka P. Szremska ◽  
Lukas Kenner ◽  
Eva Weisz ◽  
Rene G. Ott ◽  
Emmanuelle Passegué ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Transgenic Animals ◽  
Inhibitory Effect ◽  
Lymphoid Cells ◽  
Negative Regulator ◽  
Transgenic Cells ◽  
B Lymphoid

Abstract The activator protein 1 (AP-1) member JunB has recently been implicated in leukemogenesis. Here we surveyed human lymphoma samples for expression of JunB and other AP-1 members (c-Jun, c-Fos, Fra1, JunD). JunB was strongly expressed in T-cell lymphomas, but non-Hodgkin B-cell lymphomas do not or only weakly express JunB. We therefore asked whether JunB acted as a negative regulator of B-cell development, proliferation, and transformation. We used transgenic mice that expressed JunB under the control of the ubiquitin C promoter; these displayed increased JunB levels in both B- and T-lymphoid cells. JunB transgenic cells of B-lymphoid, but not of T-lymphoid, origin responded poorly to mitogenic stimuli. Furthermore, JunB transgenic cells were found to be less susceptible to the transforming potential of the Abelson oncogene in vitro. In addition, overexpression of JunB partially protected transgenic mice against the oncogenic challenge in vivo. However, transformed B cells eventually escaped from the inhibitory effect of JunB: the proliferative response was similar in explanted tumor-derived cells from transgenic animals and those from wild-type controls. Our results identify JunB as a novel regulator of B-cell proliferation and transformation. (Blood. 2003;102:4159-4165)

scholarly journals Development of a murine model for blastoid variant mantle-cell lymphoma

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4899-4906 ◽  
Author(s):  
Richard J. Ford ◽  
Long Shen ◽  
Yen Chiu Lin-Lee ◽  
Lan V. Pham ◽  
Asha Multani ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Murine Model ◽  
Cell Lymphoma ◽  
Immunoglobulin Gene ◽  
B Cell Lymphomas ◽  
Mantle Cell ◽  
B Cell Growth Factor ◽  
The Brain

Abstract Blastoid-variant mantle-cell lymphoma (MCL-BV), unlike most B-cell non-Hodgkin lymphomas (NHL-Bs), is refractory to conventional chemotherapy and associated with a very poor prognosis. Development of new therapies has been hampered by the lack of valid animal models. We have developed a novel murine model of MCL-BV by crossing interleukin 14α (IL-14α) transgenic mice with c-Myc transgenic mice (double transgenic [DTG]). IL-14α is a B-cell growth factor that is expressed in a number of high-grade lymphomas, including MCL-BV. Ninety-five percent of IL-14α transgenic mice develop CD5+ large B-cell lymphomas by 18 months of age. Sixty percent of c-Myc transgenic mice develop pre-B-cell lymphomas by 12 months of age. Close to 100% of DTG mice develop an aggressive, rapidly fatal lymphoma at 3 to 4 months of age that is CD5+, CD19+, CD21−, CD23−, sIgM+. The tumor is found in the blood, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and lungs and rarely in the brain, similar to the involvement seen in human MCL-BV. Immunoglobulin gene rearrangements document the monoclonality of the tumor. Cyclin D1 is highly expressed in these tumors, as it is in MCL-BV. DTG represents a novel model for MCL-BV that should reveal important insights into the pathogenesis of the lymphoma and contribute to the development of new forms of therapy.

scholarly journals SOX11 Cooperates with CCND1 in Mantle Cell Lymphoma Pathogenesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1253-1253 ◽  
Author(s):  
Pei-Yu Kuo ◽  
Zewei Jiang ◽  
Deepak Perumal ◽  
Violetta V Leshchenko ◽  
Alessandro Lagana' ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
B Cell ◽  
Transgenic Mouse ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Sox11 Expression

Abstract MCL (Mantle cell lymphoma) is an aggressive and incurable B cell malignancy with a median survival of 5-6 years. Cyclin D1 (CCND1) overexpression is a key diagnostic feature of this disease, observed in more than 90% of MCL tumors. However, murine models over-expressing CCND1 in B cells do not recapitulate the phenotype of MCL. The SOX11 transcription factor is aberrantly expressed in 80-90% of primary MCL. Our published data demonstrated that SOX11 binds and functionally regulates key components in multiple oncogenic pathways in MCL such as WNT and TGFβ pathways. Recent studies have also showed that SOX11 regulates PAX5 and PDGFA to block differentiation and facilitate lymphoma growth. We thus hypothesize that SOX11 expression may contribute directly and functionally cooperate with CCND1 in MCL pathogenesis. To study the role of SOX11 in MCL tumorigenesis in vivo, we have generated a novel SOX11 transgenic mouse model with B cell-specific tissue expression under the E-mu enhancer and an IRES-eGFP tag to monitor the expression of SOX11. The presence of SOX11 can be readily detected in pre-pro-B stage in the bone marrow coincided with the activation of E-mu enhancer and was persistent through all stages of B cells. SOX11 over-expression in our mouse model led to an aberrant oligo-clonal expansion of CD19+/CD5+ B cells. This phenotype was evident in all SOX11 transgenic mice studied (100% penetrance, n= 42 mice) with an average of 7-12 fold increase (p<0.03) of the CD5+ B cell populations as compared to littermate controls starting from 1.5 months. Using Mass Cytometry (CyTOF), we further characterized this B cell population to be CD23-, CD21/35 dim, CD138-, high surface IgM, and variable IgD expression, a naive B cell phenotype consistent with an early precursor stage of human MCL. This MCL phenotype is most prominent in peripheral blood and spleen and, to a much lesser extent, in peritoneal cavity and bone marrow. Transplanting bone marrow from SOX11 transgenic mouse to lethally-irradiated wild type mice successfully transferred the observed phenotypic CD19+/CD5+/CD23- B cell hyperplasia, suggesting that SOX11 overexpression in early B cells drives this MCL phenotype. We next studied the cooperation between CCND1 and SOX11 by crossing SOX11 transgenic mice with a CCND1 transgenic mouse model, which over-expresses CCND1 in a B-cell specific manner under a similar E-mu enhancer. Overexpression of both CCND1 and SOX11 in the double transgenic mice model dramatically enhanced (average 10x, range 6x-30x) the aberrant MCL phenotype (CD19+/CD5+/CD23-) in peripheral blood, spleen, bone marrow, peritoneal cavity and lymph nodes compared to age-matched SOX11 and CCND1 single-transgenic mice. We report here the first direct evidence in vivo that SOX11 expression drives an aberrant expansion of B cells consistent with early human MCL and functionally collaborates with CCND1 in "full blown" MCL pathogenesis, mimicking the commonly observed co-expression of SOX11 and CCND1 in most human MCL tumors. This model captures the underpinning molecular pathogenesis events occurred in the majority of human MCL and overcomes constraints of previous MCL models that develop a phenotype after long latency or with low penetrance, making it a valuable tool for testing anti-MCL therapeutics. We are currently developing small molecule SOX11 inhibitors using SOX11 DNA binding domain models and consensus SOX11 binding nucleotides to screen a large library of compounds to identify new therapeutics for this fatal disease and gain better understanding of the molecular mechanisms of MCL tumorigenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD24/Siglec-10 "Don't Eat Me" Signal Blockade Is a Potential Immunotherapeutic Target in Mantle-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2276-2276
Author(s):  
Andrea Aroldi ◽  
Mario Mauri ◽  
Matteo Parma ◽  
Elisabetta Terruzzi ◽  
Marilena Fedele ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Target Cells ◽  
Solid Cancer ◽  
Dismal Prognosis ◽  
Mantle Cell

Abstract Introduction Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) characterized by heterogenous behavior, ranging from indolent phenotype to highly aggressive and drug resistant one with dismal prognosis. Drug resistance may be generated by Tumor Microenvironment (TME), owing that Tumor-Associated Macrophages (TAM) are pathologically functional in providing survival signals to MCL cells (Pham, Front Oncol. 2018). Recently, "Don't Eat Me" signal (DEMs) blockade with anti-CD47 monoclonal Antibody (moAb) showed promising activity in pretreated NHL, through increase of phagocytosis by TAM (Advani, NEJM. 2019). CD24 was also demonstrated to be involved in DEMs and, in a preclinical model of solid cancer, blocking the CD24/Siglec-10 interaction provided an improvement of M2-like TAM-mediated phagocytosis in vitro and an increase of survival in vivo (Barkal, Nature. 2019). CD24 can be expressed in some phases of B-cell differentiation and MCL derives from a B-cell precursor with upregulated CD24. To date, there are no functional studies showing an improvement of phagocytosis through CD24/Siglec-10 pathway inhibition in hematologic malignancies and MCL. Here, we present our in vitro results of CD24/Siglec-10 DEMs blockade in MCL subset. Methods A panel of MCL cell lines (Jeko-1, Granta-519, Mino) has been analyzed for CD24 surface expression by flow cytometry (FC) (clone SN3). Consequently, we performed co-culture experiments with MCL cell lines and macrophages from healthy donors. Briefly, Peripheral Blood Mononucleated Cells (PBMC) were collected from healthy volunteers through density gradient centrifugation technique. CD14+ monocytes were isolated through CD14 Microbeads isolation kit and cultured in plates with 50 ng/ml human GM-CSF for 7-9 days. In order to create M2-like Siglec-10+ TAM, 50 ng/ml human IL-10 and 50 ng/ml human TGF-β 1 were added on days 3-4 of differentiation until use on days 7-9. Siglec-10 expression on TAM was checked by FC (clone 5G6). M2-like macrophages were then collected and co-cultured with CFSE-labelled MCL target cells for 1-2 hours in a serum-free medium. Anti-CD24 moAb (clone SN3) or the appropriate IgG 1 isotype control were added at a concentration of 10 μg/ml. Phagocytosis was then stopped on ice and CD11b-PE staining (anti-CD11b moAb, clone REA713) was performed to identify human macrophages by FC. Phagocytosis was measured as the number of CD11b+/CFSE+ macrophages, quantified as a percentage of the total CD11b+ macrophages. Each phagocytosis reaction was performed in technical triplicate and phagocytosis was normalized to the highest technical replicate per donor in order to consider raw phagocytic level among donor-derived macrophages. Results MCL cell lines express surface CD24 by FC, with higher levels in Mino cell line (Figure 1A). Differentiated M2-like macrophages showed an upregulation of Siglec-10 expression after immunosuppressive stimuli, which is fundamental owing that Siglec-10 is the ligand of CD24 (Figure 1B). As pertains to the phagocytic assay, we documented an improvement of phagocytosis when M2-like macrophages and MCL cell lines were co-cultured together with anti-CD24 moAb (Figure 2 and Figure 3A). Furthermore, it is worth mentioning that phagocytosis seemed to be much higher in MCL cell lines with higher surface levels of CD24 (e.g., Mino), presenting increased number of CD11b+/CFSE+ M2-like TAM by FC (Figure 3B). Conclusions MCL was found to be sensitive to CD24/Siglec-10 DEMs blockade when co-cultured with M2-like macrophages in vitro. We can argue that most of the observed increase of phagocytosis after the addition of anti-CD24 moAb may be secondary to loss of CD24 signalling rather than Fc-mediated opsonization, as already documented in previous analysis about solid cancer (Barkal, Nature. 2019). We can therefore hypothesize that the blockade of this DEMs pathway can improve phagocytosis in a non-opsonization manner in NHL as well. Furthermore, CD24 surface density seemed to be positively correlated to the intensity of phagocytic activity, suggesting that MCL subtypes expressing higher CD24 levels are much more dependent on this DEMs pathway than others with low CD24 density. Overall, CD24 turned out to be a potential immunotherapeutic target in MCL, aiming at improving innate immune system through DEMs blockade. In vivo studies are needed to confirm the activity we documented in vitro in this NHL subset. Figure 1 Figure 1. Disclosures Gambacorti-Passerini: Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

“Small” B-cell Non-Hodgkin's Lymphomas with Splenomegaly at Presentation Are Either Mantle Cell Lymphoma or Marginal Zone Cell Lymphoma

1996 ◽  
Vol 20 (2) ◽  
pp. 211-223 ◽  
Author(s):  
Stefania Pittaluga ◽  
Gregor Verhoef ◽  
Arnold Criel ◽  
Iwona Wlodarska ◽  
Judith Dierlamm ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Zone Cell ◽  
Hodgkin's Lymphomas

Combined Inhibition of CDK and PI3K/Akt Pathways Induces Apoptosis of Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1384-1384
Author(s):  
Subhra Mohapatra ◽  
Baoky Chu ◽  
Xiuhua Zhao ◽  
Jianguo Tao ◽  
Eduardo Sotomayor ◽  
...  
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Tumor Formation ◽  
Cdk Inhibitors ◽  
Akt Inhibitor ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas

Abstract Mantle cell lymphoma (MCL) arises from the neoplastic transformation of naïve B cells in the mantle zone of the B cell follicle. It is an aggressive and incurable B cell neoplasm. It accounts for 5% to 8% of non-Hodgkin’s lymphomas. Patients with MCL respond initially to chemotherapy but ultimately relapse. Mean survival time is only three to four years. Thus, the need for new treatments that effectively combat MCL is obvious and imperative. Defects in cell cycle regulation and apoptosis are primary events in MCL. It is characterized by the presence of a chromosomal translocation t (11:14)(q13:q32), which results in deregulated cyclin D1 expression. Cyclin D1 overexpression in MCL is thought to play a major role in lymphomagenesis, although the precise mechanisms by which tumor formation and progression occur are not fully understood. Constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis and survival of MCL. Activated AKT was found in cultured MCLs as well as in 100% of aggressive-blastoid variants of MCL tumors, compared to 30% of typical MCLs. Towards the search for novel therapies for MCLs, we examined the potential of roscovitine (rosc) or flavopiridol (flav), inhibitors of cyclin dependent kinase (CDK), as a single agent or in combination with LY294002 (LY), a PI3K/Akt inhibitor, in inducing apoptosis of various MCL lines as well as in MCL patient samples. CDK inhibitors modestly increased the percentage of apoptotic cells (∼30%), whereas LY had no effect. However, when added in combination, rosc/LY or flav/LY induced apoptosis in more than 70% of cells. In an effort to understand the mechanism of apoptosis, we identified three targets: cyclin D1, the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and X-linked Inhibitor of Apoptosis (XIAP). CDK inhibitors eliminated Mcl-1 expression, slightly reduced XIAP abundance and had very little effect on abundance of cyclin D1. Conversely, LY reduced cyclin D1 expression and slightly reduced the abundance of Mcl-1 and XIAP. A larger decrease in XIAP abundance is seen in cultures treated with a combination of rosc/LY or flav/LY. On the basis of these findings, we suggest that agents that target Mcl-1, XIAP and cyclin D1 will be most effective in inducing apoptosis of human MCLs.

Establishment of a New Mantle Cell Lymphoma Cell Line That Has Epigenetically Silenced CD20 As a Resistance Mechanism in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4619-4619
Author(s):  
August Stuart ◽  
Kamal Sharma ◽  
Sara Shimko ◽  
Zainul Hasanali ◽  
Elliot M Epner
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Epigenetic Mechanism ◽  
Significant Activity ◽  
Antitumor Effects ◽  
Mantle Cell

Abstract Abstract 4619 Rituximab is an anti-CD20 monoclonal antibody that has significant activity in B cell lymphomas that express the cell surface protein CD20. The mechanism of its antitumor effects in vivo are not clear but include direct apoptotic effects, complement mediated cytotoxicity (CMC), and antibody dependent cellular cytotoxicity (ADCC). Previously we initiated a clinical trial of SAHA (vorinostat), cladribine, and rituximab (SCR) in patients with CD20+ B cell malignancies. In addition to its cytotoxic effects, recent evidence suggests that 2-CdA has hypomethylating properties. A 65 year old patient with newly diagnosed blastic,leukemic, mantle cell lymphoma (MCL) was initiated on the SCR trial. He responded promptly with normalization of his blood counts and resolution of his splenomegaly. A PET/CT scan performed prior to cycle 3 was consistent with a complete metabolic remission. He developed cytopenias prior to cycle 5 that met criteria for removal from the study. Imaging and blood studies were compatible with florid relapse of his MCL including CNS disease. At post mortem analysis, cells in the CNS were CD20 positive and cells in the blood, marrow, and lymph nodes were CD20 negative by immunohistochemistry and flow cytometry. CD20 mRNA analysis by qRT-PCR demonstrated marked reduction in CD20 mRNA. A cell line was derived from the patient's blood. The cells are cyclin D1 positive and expresses Sox 11 with ∼50 times less CD20 mRNA and appropriate sized protein. This 353 cell line has been grown in continuous culture for > 1 year and remains CD20 negative, CCND1 positive and contains the t(11;14). Analysis of the CD20 promoter and coding region demonstrated no evidence of a deletion or point mutation. Chromatin immunoprecipation (ChIP) assays were performed to access epigenetic changes at the CD20 promoter. First, we showed that the CD20 promoter in Granta MCL cells treated with cladribine contain decreased amounts of methylated histones H3K9 and K27, consistent with an epigenetic mechanism of action of cladribine involving histone methylation. Decreased DNA methylation at the CD20 promoter was also observed. ChIP analysis of the patient's cells before and after treatment with cladribine and vorinostat in vivo demonstrated decreases in CD20 promoter DNA and histone (H3 K9 and H3K27) methylation, consistent with the known epigenetic properties of these agents. The 353 cell line reported here will be of interest in studying epigenetic mechanisms of resistance to rituximab by silencing of CD20 gene expression. Experiments to overexpress exogenous CD20 to resensitize 353 cells to rituximab are in progress and will be reported. Future experiments will also aim at identifying a cDNA or drug that can overcome epigenetic resistance in vitro in 353 cells. These experiments could lead to improved treatments to overcome epigenetically mediated resistance to rituximab. Disclosures: No relevant conflicts of interest to declare.

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