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

Most human lymphomas remain heterogeneous biologic entities in spite of recent advances in the description of their clinical presentation, cellular morphology, immunophenotype, and genotype. Elucidation of genetic alterations causing malignant transformation may explain pathogenesis, refine differential diagnosis, clarify prognosis, and provide rational basis for new therapy. During the last year the expression of anaplastic lymphoma kinase clarified presentation and provided clues toward the outcome of anaplastic large cell lymphoma; the breakpoints of t(2;5) were mapped; constitutive activation of anaplastic lymphoma kinase by a chromosomal inversion was described; transformation was shown to be independent of nuclear localization of anaplastic lymphoma kinase; and phospholipase C-gamma was identified as a molecular target for the kinase activity of anaplastic lymphoma kinase. Molecular characterization of recurrent chromosome abnormalities has identified new candidate oncogenes: bcl-9, bcl-10, PAX-5, MMSET, and c-maf. Their precise role in malignant transformation, and the frequency of their alteration in lymphoma and myeloma, is not yet defined. The expression of the antiapoptotic protein bcl-2 on aggressive lymphomas was shown to be associated with inferior disease-free survival by several investigators. This may be a target of pharmacologic reduction of bcl-2 levels. Can these advances in molecular pathogenesis improve cure rates for lymphoma? The spectacularly successful molecular modeling of inhibitors for HIV protease suggests that this may be an attainable objective.
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PMID:Recent advances in the molecular pathogenesis of lymphomas. 1050 66

Anaplastic Large Cell Lymphomas (ALCLs) carry translocations in which the anaplastic lymphoma kinase (ALK) gene is juxtaposed to various genes, the most common of which is the NPM/B23 gene. ALK fusion proteins result in the constitutive activation of ALK tyrosine kinase, thereby enhancing proliferation and increasing cell survival. A direct role for NPM-ALK in cellular transformation has been shown in vitro with immortalized cell lines and in vivo using retroviral transfer experiments. Nonetheless, there is no direct evidence of its oncogenic potential in T lymphocytes, which represent the most common target of ALK chimeras. Here, we describe a new mouse model of lymphomagenesis in which human NPM-ALK transcription was targeted to T cells. NPM-ALK transgenic (Tg) mice were born with the expected mendelian distribution, normal lymphoid organs, and a normal number and proportion of helper and suppressor T cells. However, after a short period of latency, all NPM-ALK Tg mice developed malignant lymphoproliferative disorders (mean survival, 18 weeks). NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms. These tumors arose in peripheral lymphoid organs (plasmacytomas) or within the bone marrow and often led to peripheral neuropathies and limb paralysis. Our NPM-ALK Tg mice are a suitable model to dissect the molecular mechanisms of ALK-mediated transformation and to investigate the efficacy of new therapeutic approaches for the treatment of human ALCL in vivo.
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PMID:NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. 1242 1

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of non-Hodgkin's lymphomas. With few exceptions (eg, anaplastic large-cell lymphoma expressing the anaplastic lymphoma kinase), PTCLs have generally been reported to have a worse prognosis compared with B-cell lymphomas. Despite the poor outcome after conventional therapy, the impact of high-dose therapy with autologous or allogeneic stem cell transplantation (SCT) in these rare diseases is poorly defined mainly because of the lack of prospective PTCL-restricted studies. Most data exist for high-dose therapy with autologous SCT in relapsing or refractory disease. Because most studies showed similar results for PTCL compared with aggressive B-cell lymphomas in which high-dose therapy with autologous SCT is accepted as standard therapy, this approach seems appropriate in relapsing or refractory PTCL. Results for high-dose therapy with autologous SCT as first-line therapy mainly rely on studies on aggressive lymphomas that also included lymphomas of the T-cell phenotype. Our own recently published PTCL-restricted prospective study confirmed the feasibility with only moderate toxicity and a good response rate. Overall, patients with a good remission status after induction therapy exhibited a high complete response rate after transplantation, and at least a subgroup of patients remained in long-term remission. The greatest uncertainty exists for the impact of allogeneic SCT after high-dose therapy. In refractory or relapsing PTCL, this approach might improve the outcome for eligible patients, especially when using reduced-intensity conditioning. Overall, because data on high-dose therapy for PTCL are limited, larger and randomized studies are necessary to definitely confirm the preliminary results.
Clin Lymphoma Myeloma 2006 Mar
PMID:The role of high-dose therapy in peripheral T-cell lymphomas. 1664 Aug 12

The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.
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PMID:GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. 1982 1

Synchronous occurrence of lymphomatous proliferations of B and T lineage in the same patient is a very rare event and still poorly understood. All the cases reported in the English language literature are described as single case reports. We report a case of 49-year-old man, with 2-year history of multiple myeloma, presented with a raised, erythematous and ulcerated nodule in the anterior aspect of his right thigh. Histologic examination of biopsy specimen showed a dense dermic infiltrate made of large balastic cells displaying anaplastic morphology with no epidermotropism. Immunohistochemical study showed that tumor cells stained positive with CD30, EMA and CD4, and negative for CD3, CD8, CD5, CD20, CD79a, CD138 and anaplastic lymphoma kinase 1 (ALK or Ki-1).
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PMID:Multiple myeloma and cutaneous anaplastic large T-cell lymphoma in the same patient: is there a causal relation? 1989 57

We present a case of pediatric anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK-positive LBCL) with a cervical, mesentery, and pelvis cavity mass. Histologic examination of the cervical mass revealed that the lesion was composed of diffuse large immunoblastic-like or plasmablastic-like tumor cells with a sinusoidal growth pattern. The tumor cells were strongly immunoreactive for ALK; revealed a granular cytoplasmic distribution; and were diffusely positive for CD45, CD4, CD138, epithelial membrane antigen, and multiple myeloma oncogene-1 but negative for CD20 and CD79a. The patient underwent 5 courses of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposid and obtained a remarkable clinical response with regression of mesentery and pelvis cavity mass. We suggest that this distinct subtype of large B-cell lymphoma should belong to the spectrum of pediatric lymphomas and that radiologic examination should be performed to inspect the progression of disease even if the patients experienced complete remission at initial chemotherapy.
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PMID:Pediatric anaplastic lymphoma kinase-positive large B-cell lymphoma: a case report and review of the literature. 2239 91

CD30-positive cutaneous lymphoproliferative disorders, a group of T-cell neoplasms, including lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma, require careful clinicopathologic correlation for diagnosis. An association between LyP and the development of a second hematolymphoid malignancy has been established in the literature. LyP has also been reported with systemic amyloidosis, but no such reports have documented coexisting cutaneous amyloid deposition with LyP to our knowledge. A 66-year-old woman with cutaneous amyloidosis, secondary to multiple myeloma, in remission, presented with erythematous and dark-brown papules involving the right arm, scalp, and torso. Punch biopsy of the arm showed a dermal infiltrate of intermediate-sized lymphocytes, some of which displayed a plasmacytoid morphology and prominent nodular subepidermal amyloid deposition. Punch biopsy of the scalp similarly showed a nonepidermotropic dense dermal infiltrate of intermediate-sized plasmacytoid lymphocytes and multifocal amyloid deposition. Both infiltrates were immunophenotypically CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoproliferative processes. Subsequent studies showed no systemic involvement, and clinical correlation suggested a final diagnosis of LyP. We present this case of LyP, which histologically mimics a B-cell proliferation with a plasmacytoid morphology arising in association with cutaneous amyloidosis to highlight the importance of clinicopathologic correlation, a thorough battery of immunohistochemical studies, and consideration for a second hematologic malignancy arising in the setting of LyP.
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PMID:A Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorder Arising in a Patient With Multiple Myeloma and Cutaneous Amyloidosis. 2698 38

Plasmablastic neoplasms encompass several entities including plasmablastic lymphoma, plasmablastic plasmacytoma/multiple myeloma, primary effusion lymphoma and its extracavitary variant, anaplastic lymphoma kinase-positive large B-cell lymphoma, and Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified. Morphologically, the tumor cells are large with eccentrically located nuclei, prominent nucleoli, and basophilic/amphophilic cytoplasm. Immunophenotypically, the tumor cells express plasma cell-related antigens including CD38, CD138, interferon regulatory factor-4 (IRF4)/MUM1, PR domain zinc finger protein-1 (PRDM1), and/or X-box binding protein-1 (XBP1), with frequent loss of CD20. These tumors are diagnostically challenging for general pathologists due to their overlapping morphology and immunophenotype, and due to their rarity, and particularly so when clinical and radiologic information is insufficient. We also discuss HHV8-negative effusion-based lymphoma due to its overlapping features with primary effusion lymphoma. In this review, we focus on the useful diagnostic markers and pertinent molecular findings in these distinct entities and propose a practical diagnostic algorithm using anaplastic lymphoma kinase, HHV8, in situ hybridization for Epstein-Barr virus-encoded small RNA, immunoglobulin M, light chain stains, and clinicoradiologic criteria to avoid misdiagnosis. At the molecular level, MYC protein overexpression with or without MYC rearrangement and PRDM1-inactivating mutations or deletions are noted in a subset of such tumors, especially in plasmablastic lymphoma. Prognosis in these entities is dismal with conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Therefore, novel target therapies, such as anti-CD30 agents, and/or immune blockade therapy, are potential treatment options in the future.
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PMID:Lymphoid Neoplasms With Plasmablastic Differentiation: A Comprehensive Review and Diagnostic Approaches. 3172 18