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.

A Transgenic Mouse Model of Aggressive B-Cell Malignancy for Evaluating Anti-Human CD37 Therapeutics

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 188-188
Author(s):  
Kyle A Beckwith ◽  
Frank W Frissora ◽  
Matthew R Stefanovski ◽  
Jutta Deckert ◽  
Carlo M Croce ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Transgenic Mouse ◽  
In Vivo Studies ◽  
B Cell Malignancy ◽  
Cell Malignancy

Abstract Abstract 188 BACKGROUND: Introduction of the anti-CD20 antibody rituximab has led to remarkable progress in the development of targeted therapies for CLL and other B-cell malignancies. Despite prolonging patient survival, therapies targeting CD20 have not been curative. In recent years, alternative targets for therapeutic antibodies have emerged. One of the most promising targets has been CD37, which is highly expressed on malignant B-cells in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. The recent interest in this target has led to the generation of novel anti-CD37 therapeutics that could benefit from more extensive preclinical evaluation. However, preclinical development of these agents has been limited by the absence of appropriate leukemia animal models that provide targets expressing human CD37 (hCD37). Here we describe the development and characterization of a transgenic mouse where CLL-like leukemic B-cells express hCD37 and aggressively transplant into syngenic hosts. We demonstrate the utility of this unique mouse model by evaluating the in vivo efficacy of IMGN529, a novel antibody-drug conjugate targeting hCD37 that consists of the CD37-targeting K7153A antibody linked to the maytansinoid DM1 via the thioether SMCC linker. METHODS: The hCD37 transgenic mouse (hCD37-Tg) founder lines were generated by conventional methodology at the OSU Transgenic Facility. B-cell specific expression of hCD37 is driven by immunoglobulin heavy chain promoter and Ig-μ enhancer elements. Founder lines were evaluated by RT-PCR and flow cytometry to confirm RNA and protein expression, respectively. These lines were then crossed with the EμTCL1 mouse model of CLL to generate hCD37xTCL1 mice that develop CD5+CD19+hCD37+ leukemia. For in vivo studies, splenocytes from a leukemic hCD37xTCL1 donor were injected i.v. into healthy hCD37-Tg mice. Mice were randomly assigned to the following treatment groups (n=8–10 per group): IMGN529 conjugate, its K7153A antibody component, or negative controls (isotype antibody-DM1 conjugate or trastuzumab). Upon diagnosis of leukemia, a 10 mg/kg dose was administered i.p. and repeat doses were given 2 times per week for 3 weeks (70 mg/kg total). Peripheral blood disease was monitored by flow cytometry, using counting beads to obtain the absolute number of leukemic CD5+CD19+ B-cells. CD37 expression levels were determined by quantitative flow cytometry. In vitro cytotoxicity was evaluated after 24 hour incubation by flow cytometry with Annexin V and propidium iodide staining. RESULTS: IMGN529 and its K7153A antibody component demonstrated comparable in vitro activity against freshly isolated human CLL cells even in the absence of cross-linking agents (mean IMGN529 cytotoxicity=50.04% vs. 48.85% for K7153A; p=0.175; n=9). Both compounds also demonstrated cytotoxicity against hCD37 Tg B-cells ex vivo in a cross-linking dependent manner, and while expression of hCD37 in hCD37-Tg animals was B-cell specific, the expression levels were substantially lower than those observed in human CLL cells. In vivo studies with transferred hCD37xTCL1 splenocytes demonstrated rapid and complete depletion of CD5+CD19+ leukemic B-cells in response to IMGN529 conjugate, but not K7153A antibody treatment. After 1 week of IMGN529 treatment, peripheral blood leukemia was nearly undetectable and previously detected massive splenomegaly was no longer palpable. In contrast, leukemic counts and spleen sizes continued to increase in control cohorts. CONCLUSIONS: In summary, our group has generated a mouse model that develops a transplantable CD5+CD19+ leukemia expressing hCD37. We demonstrate the utility of this model for both in vitro and in vivo testing of therapeutics targeting hCD37. In addition, preclinical mouse studies expose the robust anti-leukemic effects of IMGN529 in this in vivo model of aggressive B-cell malignancy, despite the relatively low expression of hCD37 on the leukemic B-cells. Our engraftment model shows that IMGN529 is capable of eliminating widespread and highly proliferative mouse leukemia by a mechanism that is both CD37 antigen and conjugate dependent. Therefore, we propose that this novel therapeutic may also exhibit substantial efficacy in a wide range of human B-cell malignancies, even those with relatively low CD37 expression. [This work was supported by NIH (NM, JCB), LLS (NM, JCB) and Pelotonia (KAB)]. Disclosures: Deckert: ImmunoGen Inc.: Employment.

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.

scholarly journals Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production.

1991 ◽  
Vol 173 (2) ◽  
pp. 429-437 ◽  
Author(s):  
A Tominaga ◽  
S Takaki ◽  
N Koyama ◽  
S Katoh ◽  
R Matsumoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Aberrant Expression ◽  
Autoantibody Production ◽  
Interleukin 5 ◽  
Metallothionein Promoter ◽  
Model Mouse

Interleukin 5 (IL-5) has been suggested to be involved in the growth and differentiation of B cells and eosinophils. Especially, Ly-1+ B cells, which have been considered to produce autoantibodies, are selectively developed by this lymphokine in long-term bone marrow culture. To envisage the possible engagement of IL-5 in the development of these cells in vivo, transgenic mice carrying the mouse IL-5 gene ligated with a metallothionein promoter were generated. Transgenic mice carrying the IL-5 gene exhibited elevated levels of IL-5 in the serum and an increase in the levels of serum IgM and IgA. A massive eosinophilia in peripheral blood, bone marrow, and spleen, and an infiltration of muscle and liver with eosinophils, were observed. When cadmium-containing saline was injected intraperitoneally into transgenic mice, IL-5 production was augmented about five times within 24 h, and a distinctive Ly-1+ B cell population became apparent in the spleen after 5 d. IL-5 receptors were detected on those cells by monoclonal antibodies against IL-5 receptors. Another interesting finding in these transgenic mice was an increase in polyreactive anti-DNA antibodies of IgM class. It is suggested, therefore, that aberrant expression of the IL-5 gene may induce accumulation of Ly-1+ B cells and eosinophils. Furthermore, this IL-5 transgenic mouse can be a model mouse for eosinophilia, and we can determine the role of IL-5 in the differentiation of Ly-1+ B cells and eosinophils by using this mouse.

Genetic Loss of NFAT2 Induces Profound Acceleration of CLL in the TCL1 Mouse Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 862-862
Author(s):  
Melanie Märklin ◽  
Stefanie Bugl ◽  
Jonas S. Heitmann ◽  
Alexandra Poljak ◽  
Bettina S ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
B Cell ◽  
Peripheral Blood ◽  
Flow Cytometric Analysis ◽  
Knock Out ◽  
Flow Cytometric

Abstract Abstract 862 NFAT is a family of highly phosphorylated proteins residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. NFAT is inactivated and relocated to the cytoplasm by a network of several kinases. Although identified originally as a major transcriptional regulator in T cells, it is now clear that NFAT transcription factors also possess important roles in other cells of the hematopoietic system including dendritic cells, mast cells, megakaryocytes and B cells. Several recent studies have demonstrated that Calcineurin/NFAT signaling is involved in the pathogenesis of a wide array of hematological malignancies including diffuse large B cell lymphoma, CLL as well as Burkitt and Burkitt-like lymphomas. Here, we analyzed the role of NFAT2 in the pathogenesis of B-CLL. For this purpose, we generated mice with a conditional NFAT2 knock out allele (NFAT2fl/fl). In order to achieve NFAT2 deletion limited to the B cell lineage, we bred NFAT2fl/fl mice to CD19-Cre mice, in which the Cre recombinase is expressed under the control of the B cell-specific CD19 promoter. To investigate the role of NFAT2 in the pathogenesis of CLL we made use of the Eμ-TCL1 transgenic mouse model in which the TCL1 oncogene is expressed under the control of the Eμ enhancer. TCL1 transgenic mice develop a human-like CLL at the age of approximately 14 weeks to which the animals eventually succumb at an average age of 10 months. To analyze the role of NFAT2 in CLL, we generated mice (n=10) whose B cells exhibited a specific deletion of this transcription factor in addition to their transgenic expression of the TCL1 oncogene (TCL1 CD19-Cre NFAT2fl/fl). TCL1 transgenic mice without an NFAT2 deletion served as controls (n=10). Mice with NFAT2 knock out exhibited a significantly accelerated accumulation of CD5+CD19+ CLL cells as compared to control animals. Flow cytometric analysis at distinct time points showed a tremendous infiltration by CD5+ B cells in the peritoneal cavity, spleen, lymph nodes, liver and bone marrow which was significantly stronger in the NFAT2 ko cohort. Most of the CD5+ B cells in TCL1+NFAT2 ko mice showed high expression of ZAP70 and CD38, whereas TCL1 transgenic mice only demonstrated very few CD5+ B cells with concomitant expression of ZAP70 and CD38. At approximately 26 weeks of age, NFAT2 ko mice showed an approximately 40 fold increased lymphocyte count in the peripheral blood than their litter mate controls (1500/μL vs. 60000/μL). Splenomegaly and lymphatic adenopathy was also significantly increased in the NFAT ko population. Furthermore, NFAT2 ko mice showed a dramatically reduced median survival (200 vs. 325 days) and maximum survival (265 vs. 398 days) in comparison to regular TCL1 transgenic mice. To investigate the effects of an NFAT2 ko on proliferation and apoptosis of CD5+CD19+ CLL cells, we performed in vivo BrdU incorporation assays with subsequent flow cytometric analysis. Interestingly, we could show that CLL cells isolated from spleens, bone marrow and peripheral blood from mice with an NFAT ko at an age of approximately 7 months exhibited significantly higher rates of proliferation than control animals. In summary, our data provide strong evidence that NFAT2 is a critical regulator of CD38 and ZAP70 expression and substantially controls cell cycle progression in CLL cells implicating Ca2+/NFAT signaling as a potential target for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4532-4541 ◽  
Author(s):  
Michael Hudecek ◽  
Thomas M. Schmitt ◽  
Sivasubramanian Baskar ◽  
Maria Teresa Lupo-Stanghellini ◽  
Tetsuya Nishida ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Chimeric Antigen Receptor ◽  
Cell Lymphoma ◽  
Embryonic Stem ◽  
Antigen Receptor ◽  
Orphan Receptor ◽  
Mantle Cell

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4503-4506 ◽  
Author(s):  
Anja Mottok ◽  
Christoph Renné ◽  
Marc Seifert ◽  
Elsie Oppermann ◽  
Wolf Bechstein ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Rare Mutations ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Follicular Lymphomas ◽  
Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

scholarly journals Antigen-Specific B Cell Memory

2000 ◽  
Vol 191 (7) ◽  
pp. 1149-1166 ◽  
Author(s):  
Louise J. McHeyzer-Williams ◽  
Melinda Cool ◽  
Michael G. McHeyzer-Williams
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Memory B Cells ◽  
Cell Memory ◽  
Specific Memory ◽  
B Cell Memory ◽  
Cellular Components

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220−CD138−) that are distinct from antibody-secreting B cells (B220+/−CD138+) and B220+CD138− memory B cells. These nonsecreting somatically mutated B220− memory responders rapidly dominate the splenic response and comprise &gt;95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75–85%) and the bone marrow (&gt;95%) expresses the B220− phenotype. Upon adoptive transfer, B220− memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220+ counterparts. The pattern of cellular differentiation after transfer indicates that B220− memory B cells act as stable self-replenishing intermediates that arise from B220+ memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220− compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.

Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 864-869 ◽  
Author(s):  
Michele Magni ◽  
Massimo Di Nicola ◽  
Liliana Devizzi ◽  
Paola Matteucci ◽  
Fabrizio Lombardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Hematopoietic Stem ◽  
Mantle Cell

Abstract Elimination of tumor cells (“purging”) from hematopoietic stem cell products is a major goal of bone marrow–supported high-dose cancer chemotherapy. We developed an in vivo purging method capable of providing tumor-free stem cell products from most patients with mantle cell or follicular lymphoma and bone marrow involvement. In a prospective study, 15 patients with CD20+ mantle cell or follicular lymphoma, bone marrow involvement, and polymerase chain reaction (PCR)–detectable molecular rearrangement received 2 cycles of intensive chemotherapy, each of which was followed by infusion of a growth factor and 2 doses of the anti-CD20 monoclonal antibody rituximab. The role of rituximab was established by comparison with 10 control patients prospectively treated with an identical chemotherapy regimen but no rituximab. The CD34+ cells harvested from the patients who received both chemotherapy and rituximab were PCR-negative in 93% of cases (versus 40% of controls;P = .007). Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical and molecular remission in all 14 evaluable patients, including all 6 with mantle cell lymphoma (versus 70% of controls). In vivo purging of hematopoietic progenitor cells can be successfully accomplished in most patients with CD20+ lymphoma, including mantle cell lymphoma. The results depended on the activity of both chemotherapy and rituximab infusion and provide the proof of principle that in vivo purging is feasible and possibly superior to currently available ex vivo techniques. The high short-term complete-response rate observed suggests the presence of a more-than-additive antilymphoma effect of the chemoimmunotherapy combination used.

scholarly journals B lymphocytes express and lose syndecan at specific stages of differentiation.

1989 ◽  
Vol 1 (1) ◽  
pp. 27-35 ◽  
Author(s):  
R D Sanderson ◽  
P Lalor ◽  
M Bernfield
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Receptor Expression ◽  
Cell Stage ◽  
Precursor B Cells

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

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