Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pax5, or B-cell-specific activator protein, is a nuclear protein in the paired-box containing (PAX) family of transcription factors involved in control of organ development and tissue differentiation. Pax5 is mostly expressed in B lymphocytes and B-cell lymphomas, although recent data have shown expression in the developing central nervous system, some neuroendocrine tumors, and occasional myeloid leukemias. Pax5 immunohistochemistry shows robust nuclear staining, and has become a valuable tool in the diagnosis and subclassification of lymphomas. Pax5 staining is positive in most Hodgkin and B-cell non-Hodgkin lymphomas, and also precursor B-cell lymphoblastic neoplasms. Plasma cell neoplasms, multiple myeloma, and plasmablastic lymphomas typically are negative. T-cell lymphomas are, to date, consistently negative. Recently, Pax5 expression has been described in the majority of small cell carcinomas and Merkel cell carcinomas. Rare cases of Pax5 expression in other carcinomas have been reported. With these exceptions, Pax5 immunohistochemistry is fairly specific for B-cell lineage and is a valuable addition to the armamentarium of markers available for lymphoma subtyping.
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PMID:Diagnostic uses of Pax5 immunohistochemistry. 1771 32

Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.
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PMID:Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. 1850 36

Aberrant expression of cytokeratins (CK) is known to occasionally occur in malignant lymphomas. The monoclonal mouse-anti-human CK cocktail CK22 recognizes keratin polypeptides with a wide range of molecular weights and can be applied in diagnostic panels for tumors of unknown origin. Using tissue microarray technology, we tested 1059 lymphoma and acute leukemia cases, covering the most common disease entities, for aberrant CK expression, using CK22. In total, 866 of the arrayed cases were evaluable (80%), and 13 positive cases (1.5%) were found: 1 out of 230 Hodgkin lymphomas (0.4%), 1 plasma cell myeloma, 2 out of 326 diffuse large B-cell lymphomas (0.6%), 5 out of 18 mantle cell lymphomas (26%), 3 out of 70 small cell lymphomas/chronic lymphocytic leukemias (4%) and 1 out of 27 peripheral T-cell lymphomas, not otherwise specified (4%). Immunostaining was finely granular in most cases, and the total amount of positively staining cells exceeded 10% only in the cases of Hodgkin lymphoma and plasmocytoma. All CK22-positive cases, except for one mantle cell lymphoma, expressed the specific simple epithelial CK8 but not the basal/stratified epithelial CK5/6. Aberrant CK expression can be encountered in a small subset of otherwise characteristic B- and T-cell lymphomas, but not in acute leukemias, which should be considered in difficult differential diagnostic settings.
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PMID:Cytokeratin expression in hematological neoplasms: a tissue microarray study on 866 lymphoma and leukemia cases. 1843 89

The purpose of this study was to find histological clues for reliable differentiation between monoclonal gammopathy of undetermined significance (MGUS) and myeloma when clinical parameters are controversial. Differential appearance of dendritic cells and osteoclasts, two cell types developing from the monocytic lineage upon distinct cytokine activation profile, might be a useful approach. Bone and bone-marrow biopsies performed in 105 patients were studied using histomorphometry after identification of osteoclasts (by histochemical identification of tartrate resistant acid phosphatase) and dendritic cells (by immunohistochemical detection of the S-100 protein). Patients were classified by the World Health Organization criteria but histopathological criteria were more adapted to identify MGUS (53 cases), myeloma (46), B-cell lymphoma (six) since six myeloma were not correctly classified. Histomorphometry was compared to 15 control cases. The number of marrow dendritic cell was significantly increased with B-cell lymphoma >MGUS >myeloma > controls. Dendritic cell were often mixed with lymphoma cells. Myeloma had increased bone resorption with a high osteoclast number and moderate increase in dendritic cells. B-cell lymphomas had a considerable increase in dendritic cell but presented mononucleated osteoclasts. These findings can help in the classification of MGUS in the early stages of the disease and could help to propose preventive treatments.
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PMID:Quantification of dendritic cells and osteoclasts in the bone marrow of patients with monoclonal gammopathy. 1875 46

Monoclonal antibodies are expanding the therapeutic options for patients with B-cell lymphoma. Despite the antitumor activity of rituximab alone or in combination with systemic chemotherapy against various subtypes of B-cell lymphomas, a significant number of patients relapse or do not respond to initial therapy, stressing the need to identify novel molecular targets. CD80 is a surface glycoprotein and a member of the B7 family of costimulatory molecules. CD80 antigen is expressed in antigen-presenting cells, normal B cells, and various subtypes of B-cell lymphomas. Moreover, CD80 is an important regulator of T-cell activation. In addition, in vitro binding of CD80 by specific monoclonal antibodies (MoAbs) results in growth inhibition and apoptosis of normal and malignant B cells. Galiximab is a primatized MoAb targeting CD80. Preclinical studies had shown significant antitumor activity as a single agent or in combination with rituximab against various B-cell lymphoma cell lines in vitro and in vivo. An initial phase I/II study with galiximab as a single agent in patients with relapsed B-cell lymphoma demonstrated its safety and antitumor activity and had provided a framework for future studies. Interestingly, and in contrast with what had been observed with other biologic agents, the time to best response for the responding patients was delayed, suggesting an alternative mechanism of action other than the traditional antibody-dependent cellular cytotoxicity, apoptosis, and complement-mediated cytotoxicity. Ongoing and future studies are warranted to further evaluate the therapeutic role of galiximab in the treatment of patients with B-cell lymphomas in combination with rituximab or systemic chemotherapy.
Clin Lymphoma Myeloma 2008 Oct
PMID:The use of galiximab in non-Hodgkin lymphoma. 1885 81

Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.
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PMID:Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas. 1898 57

Aside from Myc-activating translocations characteristic of plasmacytomas (PCT), little is known about genetic factors and signaling pathways responsible for the development of spontaneous B-cell lineage lymphomas of mice. Here, we characterized the transcriptional profiles of PCT, centroblastic diffuse large B-cell lymphomas (CBL), and high-grade splenic marginal zone B-cell lymphoma (MZL++) using high-throughput quantitative reverse transcription-PCR. Expression profiles of CBL and MZL++ were strikingly similar and quite unlike that of PCT. Among the genes expressed at significantly higher levels by PCT were a number involved in NOTCH signaling, a finding supported by gene set enrichment analyses of microarray data. To investigate the importance of this pathway, NOTCH signaling was blocked in PCT cell lines by treatment with a gamma-secretase inhibitor (GSI) or transduction of a dominant-negative mutant of MAML1. These treatments resulted in reduced expression of NOTCH transcriptional targets in association with impaired proliferation and increased apoptosis. GSI treatment of transformed plasma cells in a primary PCT also induced apoptosis. These results integrate NOTCH activation with oncogenic signaling pathways downstream of translocated Myc in the pathogenesis of mouse PCT, two signaling pathways also implicated in development of human multiple myeloma and T-cell lymphoblastic lymphoma.
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PMID:NOTCH is part of the transcriptional network regulating cell growth and survival in mouse plasmacytomas. 1901 Aug 92

Multiple myeloma (MM) and plasmacytomas are cancers of antibody-secreting cells (ASCs). PRDM1/BLIMP1 is an essential regulator of ASC development. Histologic evidence shows that 100% of MM expresses PRDM1/BLIMP1, indicating that PRDM1/BLIMP1 is important for the development or persistence of MM. In contrast, some diffuse large B-cell lymphomas (DLBCLs) lose PRDM1 expression, suggesting that PRDM1 may act as a tumor suppressor in DLBCL. Thus, the role of PRDM1/BLIMP1 in transformation of mature B cells is unclear. We have used a plasmacytoma-prone transgenic mouse model to study the effect of Blimp1 loss on plasmacytoma prevalence, latency, and phenotype. Two possible outcomes could be envisaged: loss of Blimp1 might decrease plasmacytoma prevalence, through reduction of plasma cells, and so the number of susceptible transformation targets. Alternatively, Blimp1 may participate in the transformation process itself. Our results support the latter scenario, showing that decreasing Blimp1 dosage does not change plasma cell number in nontransgenic mice in vivo, but it significantly reduces plasmacytoma prevalence in transgenic mice. Loss of functional Blimp1 completely prevents plasmacytoma formation in this tumor model. These observations suggest that Blimp1 is limiting for plasma cell transformation and thus has potential as a target for new therapies to combat MM.
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PMID:Blimp1 is limiting for transformation in a mouse plasmacytoma model. 1932 82

Dacetuzumab, a humanized mAb targeting the CD40 antigen, is in development by Seattle Genetics Inc and licensee Genentech Inc for the potential treatment of hematological malignancies. The CD40 antigen is a highly expressed cell surface transmembrane protein that is present in normal B-cells. Experiments using blocking antibodies for the CD40 ligand demonstrated that CD40 signaling may play a role in the development and maintenance of B-cell hematological malignancies and some solid tumors. In vitro, dacetuzumab exhibited antitumor activity against several B-cell lymphoma and multiple myeloma (MM) cell lines, and induced direct apoptosis as well as the engagement of effective antibody-dependent cell-mediated cytotoxicity. In vivo, dacetuzumab demonstrated enhanced antitumor efficacy in combination with other mAbs and chemotherapeutic agents; many of these combinations are now being tested clinically. Early clinical trials have evaluated the pharmacokinetics, safety and efficacy of dacetuzumab monotherapy in patients with relapsed/refractory B-cell lymphomas or MM. Targeting CD40 with dacetuzumab resulted in modest antitumor activity in B-cell lymphomas and, to a lesser extent, in MM. In particular, patients with diffuse large B-cell lymphoma responded well to dacetuzumab; the drug is being pursued for this indication in phase II trials.
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PMID:Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies. 1951 47

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. wedge chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions.
Clin Lymphoma Myeloma 2009 Jun
PMID:Primary central nervous system mucosa-associated lymphoid tissue lymphoma: case report and literature review. 1952 85


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