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.

scholarly journals Mantle Cell Lymphoma Presenting as Acute Abdominal Syndrome: A Rare Case Report and Literature Review

Healthcare ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1000
Author(s):  
Fu-Chou Lee ◽  
Junn-Liang Chang ◽  
Hung-Ming Chen ◽  
Wan-Chen Tsai ◽  
Po-Jen Hsiao
Keyword(s):  
Acute Appendicitis ◽  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Lower Quadrant ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas ◽  
Right Lower Quadrant

Background: Acute abdominal syndrome can be caused by several possible reasons. The most common causes are perforation of a gastroduodenal ulcer, peritonitis, intestinal obstructions, and perforation of an appendix or fallopian tube. Fever and pain can be caused by an appendicitis or sigmoiditis. Appendiceal lymphoma is a rare disease that is usually found incidentally during appendectomy. Most of the cases are non-Hodgkin’s lymphomas. Mantle cell lymphoma is an aggressive B-cell non-Hodgkin’s lymphoma with a poorer prognosis than other B-cell lymphomas; thus, a definitive diagnosis is essential. Case Summary: A 60-year-old man presented with right lower quadrant pain. He denied any nausea, vomiting or anorexia and was afebrile. The physical examination revealed right lower quadrant abdomen tenderness. The computed tomography scan revealed periappendiceal fatty stranding with a swollen appendix, approximately 2 cm in diameter and prominent paraaortic, portacaval and mesenteric lymph nodes. A diagnosis of acute appendicitis was made, and laparoscopic appendectomy was performed immediately. The subsequent pathological examination revealed severe congestion with lymphoid hyperplasia. The immunohistochemistry stains revealed positive staining for cluster of differentiation (CD) CD20, B-cell lymphoma-2 (Bcl-2), cyclin D1, SRY-box transcription factor-11 (SOX-11), immunoglobulin D (IgD) and immunoglobulin M (IgM) but negative staining for CD3, CD5, CD10 and CD23. 18F-FDG positron emission tomography showed peripheral lymph node involvement, while the bone marrow biopsy showed negative findings. Therefore, a diagnosis of mantle cell lymphoma, Ann Arbor stage IVA, was made. The patient received postoperative combination chemotherapy and remained in a stable condition over a 1-year follow-up period. Conclusion: We report an uncommon case that initially presented as acute appendicitis, for which a final diagnosis of mantle cell lymphoma was made. In comparison with other B-cell lymphomas, mantle cell lymphoma has a poorer prognosis, and positive immunochemical staining of cyclin D1 and SOX-11 is useful for differentiating mantle cell lymphoma from other appendiceal lymphomas and treating patients appropriately. Physicians and nursing staff should be also aware of the associated complications and management in these patients.

scholarly journals Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Marco Gunnellini ◽  
Lorenzo Falchi
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Response Rates ◽  
Prognostic Scores ◽  
Cell Transplant ◽  
Survival Times ◽  
Phase Ii Studies ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

SOX11 is useful in differentiating cyclin D1-positive diffuse large B-cell lymphoma from mantle cell lymphoma

2012 ◽  
Vol 61 (4) ◽  
pp. 685-693 ◽  
Author(s):  
Shih-Chuan Hsiao ◽  
Inmaculada Ribera Cortada ◽  
Luis Colomo ◽  
Hongtao Ye ◽  
Hongxiang Liu ◽  
...  
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Large B Cell

Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 129-129 ◽  
Author(s):  
Thomas Witzig ◽  
Susan Geyer ◽  
Irene Ghobrial ◽  
David Inwards ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Median Time ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Pi3k Pathway ◽  
Mantle Cell ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

Herpes Zoster (HZ) Complicating Bortezomib Therapy of Relapsed/Refractory Indolent B-Cell and Mantle Cell Lymphoma: An Analysis of Two Phase II Trials.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2818-2818
Author(s):  
Vicki A. Morrison ◽  
Richard I Fisher ◽  
Andre Goy ◽  
Sven de Vos ◽  
Steven H. Bernstein ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Purine Analog

Abstract Abstract 2818 Background: The use of bortezomib-based therapy is known to be associated with an increased risk of HZ in patients (pts) with multiple myeloma, who have disease-related inherent immune defects. A 13% incidence of HZ occurrence in pts with relapsed/refractory MM who received single agent bortezomib has been previously reported (J Clin Oncol 2008; 26:4784-4790). However, the occurrence of HZ in bortezomib-treated pts with non-Hodgkin lymphoma (NHL) has not been previously examined. Methods: We reviewed clinical data from two phase II trials in which bortezomib therapy was administered to pts with relapsed/refractory mantle cell NHL or indolent B-cell NHL. The occurrence of HZ complicating their treatment course was delineated, and an analysis for potential predisposing risk factors was undertaken. Results: A total of 236 relapsed/refractory pts, median age 65 years (yrs), enrolled on these trials was examined. Mantle cell NHL pts (n=155) received single-agent bortezomib, 1.3 mg/m2, days (D) 1, 4, 8, 11, 21-D cycles; those with indolent B-cell NHL (n=81) received either bortezomib, 1.3 mg/m2, D 1, 4, 8, 11, 21-D cycles, plus rituximab, 375 mg/m2, D 1, 8, 15 (cycle 1) and D 1 (cycle 2) (n=41), or bortezomib, 1.6 mg/m2, D 1, 8, 15, 22, 35-D cycles, and rituximab, 375 mg/m2, D 1, 8, 15, 22 (cycle 1) (n=40). HZ occurred in 24 pts (10.2%) overall, with a comparable incidence in both disease subgroups. Median time to HZ occurrence was 39 (range, 11–206) days (< 2 cycles). Overall, 11% of pts had had a prior episode of HZ. Baseline demographic and clinical variables were examined, including age, gender, disease stage, baseline absolute neutrophil and lymphocyte counts, hemoglobin, lactate dehydrogenase, prior HZ, and number and types of prior therapies, to determine if any may predict for subsequent development of HZ. With regard to age, 71% of pts with HZ were age ≥65 yrs, compared to 48% without HZ (p=0.03). 63% of pts with HZ had received ≥2 lines of prior therapy, compared to 47% in those without HZ (p=0.15). 4% of pts with HZ had undergone prior stem cell transplantation, compared to 13% of pts without HZ. Of the pts with HZ, 25% had received prior purine analog therapy, compared to 9% of pts without HZ. The other baseline variables had no impact on the occurrence of HZ. In the 77 pts who responded to bortezomib protocol therapy (complete/partial responses), the incidence of HZ was 14%, compared to an 8% incidence of HZ in the 159 non-responders (p=0.15). Conclusions: HZ may complicate the course of relapsed/refractory indolent or mantle cell NHL pts receiving bortezomib-based therapies, with an incidence similar to the myeloma population. Pts who are elderly, more heavily-pretreated, or have received prior purine analog therapy may be at greater risk of this complication, and should be strongly considered for antiviral prophylaxis during such therapy. Disclosures: Morrison: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Pfizer: Speakers Bureau. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Fisher:Allos Therapeutics: Consultancy; CytoKinetics: Consultancy; GSK: Consultancy; MundiPharma: Consultancy; Seattle Genetics: Consultancy; Millennium Pharmaceuticals, Inc,: Consultancy. Goy:Millennium, Celgene, GSK and Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bernstein:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Speakers Bureau. Boral:Millennium Pharmaceuticals, Inc.: Employment; Takeda Pharmaceuticals: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment.

scholarly journals A Systemic Review of CD5-Negative Mantle Cell Lymphoma Identifies Potential Clinical and Biological Implications

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3048-3048 ◽  
Author(s):  
Arshia Soleimani ◽  
Georges Tanios ◽  
Hana Safah ◽  
Nakhle S. Saba
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Light Chain ◽  
Cell Lymphoma ◽  
Ki 67 ◽  
Female Ratio ◽  
Mantle Cell ◽  
Leukemic Phase ◽  
Male To Female

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) with a median survival of 3 to 5 years. MCL is characterized by the translocation t(11;14)(q13;32) which results in the overexpression of cyclin-D1 and ultimately an uninhibited G1/S cell cycle transition. MCL has a distinctive immunophenotype among B-cell NHL, characterized by a strong expression of the pan B-cell markers CD19 and CD20, absence of CD10 and CD23, overexpression of the anti-apoptotic protein BCL2, and aberrant expression of the T-cell marker CD5. However, up to 10% of MCL lack CD5 expression and remain ill-characterized. Whether this absence of CD5 expression impacts MCL biology and clinical course remains unknown. We performed a systematic review of all reported cases of CD5-negative MCL and analyzed their biological and clinical characteristics. Patients and methods: A systematic literature search was performed and included studies published from 1st June 1994 to 1st June 2016 in PubMed, Embase, and Web of Science. We used the key words CD5 negative, CD5-, mantle cell lymphoma, and MCL. Data was tabulated regarding the following 16 variables: t(11;14)(q13;q32), cyclin-D1, CD5, CD10, CD19, CD20, CD23, BCL2, BCL6, Ki-67 (higher or lower than 30%), IGHV mutation status (mutated IGHV >3% discordance with germline), male to female ratio, light chain expression (kappa or lambda), presence of a leukemic phase, stage, and overall survival (OS). Data was reported as percent and total number of cases with available data of each variable. Results and discussion: 68 out of 470 screened articles included CD5-negative MCL cases. After exclusion of duplicates, 50 sources (46 full articles and 4 abstracts) were included. Data of 222 cases of CD5-negative MCL were collected. To a degree, reviewed cases of CD-5 negative MCL shared similarities to classic MCL. Both sub-types had a median age at diagnosis of approximately 65 and presented as stage IV disease 70% of the time. Both subtypes overexpressed cyclin-D1 (100%, 222/222), possessed the t(11;14)(q13;q32) (93%, 49/53: 49 of 53 cases with available data on the translocation), were CD-19 positive (100%,18/18), CD20-positive (100%, 58/58), BCL2-positive (97%, 34/35), CD10-negative (93%, 42/45), and CD23-negative (95%,56/59). Presence or absence of leukemic phase was reported in 16 cases, 8 of those were positive for circulating MCL cells (50%). The proliferation marker Ki-67 was reported in 22 cases, 7 (32%) of which were >30%. CD5-negative MCL deviated from the classic MCL presentation in a number of clinical and biological variables. Most importantly, the median OS of 47 cases with available follow-up was greater than 16 years (Figure 1), which compared very favorably to the historic survival of 3 to 5 years in classic MCL. Interestingly, the number of affected males was less than expected in the CD5-negative group. Male-to-female ratio was 2:1 (74 males and 36 females of 110 cases with available gender data), which is lower than the expected 3:1 ratio. From a biological standpoint, the CD5-negative MCL cohort had more kappa than lambda-restricted cases (62%, 13 of 21 available light chain data), and more mutated than unmutated IGHV (61% mutated, 11 of 18 cases with available IGHV data). Classically, lambda-restricted MCL and unmutated IGHV are more commonly seen and were associated with worse clinical outcomes. In addition, we observed BCL6 expression in 23% of CD5-negative MCL cases, which is higher than expected (6 of 26 cases with BCL6 available data). Conclusions: To our knowledge this is the most comprehensive review of CD5-negative MCL. Lack of CD5 expression was associated with important clinical and biological differences compared to classic MCL. The higher survival observed in our analysis suggest that CD5 can potentially be incorporated in identifying a subset of a more indolent MCL that might benefit from a watch and wait approach. Currently, treatment in MCL can be differed in a subset of patients with an indolent presentation characterized by leukemic-only disease with absence of lymphadenopathy, mutated IGHV, and lack of SOX11 expression. SOX11 data was not available in our cohort, and only 18 patients had available IGHV mutation data. While the exact role of CD5 in MCL remains unknown, our findings highlight the need for a deeper investigation of CD5-negative MCL at the genetic, phenotypic, and clinical levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 268-276 ◽  
Author(s):  
LR Zukerberg ◽  
WF Benedict ◽  
A Arnold ◽  
N Dyson ◽  
E Harlow ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Adenovirus E1a ◽  
Mantle Cell

Abstract The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B- cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B- chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1–2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases showed only weak pRB expression (1 B-CLL, 1 blastoid mantle cell, 1 unclassifiable low grade B-cell lymphoma). Conversely, of the 4 pRB(+) HCLs and 3 pRB(+) plasmacytomas, only 1 of each was cyclin D1(+). pRB appeared to exist primarily in the underphosphorylated (fastest migrating) form on Western blot, despite the fact that cyclin D1 was complexed to CDK4, a form in which it normally phosphorylates pRB. In addition, pRB appeared to be unmutated, because it bound normally to the adenovirus E1A protein and showed nuclear localization by immunostaining. We conclude that most cases of mantle cell lymphoma, HCL, and plasmacytoma show high levels of pRB in contrast to follicle center lymphoma and small lymphocytic lymphoma; however, pRB expression does not appear to be consistently related to cyclin D1 overexpression. The pRB appears to be unmutated and underphosphorylated, and therefore should be in its active form. Our data from primary lymphoma tissue suggests that overexpression of cyclin D1, whereas tumorigenic, does not lead to pRB loss or hyperphosporylation. Thus, the mechanism by which cyclin D1 contributes to tumorigenesis and the significance of the restricted expression of pRB in low-grade lymphoid neoplasms remain to be determined.

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