cyclin-d1 and Hematologic-Neoplasms

Cyclin D1, encoded by CCND1, promotes cell cycle progression from G1 to S phase. Its expression is induced by MAPK/ERK pathway as well as translocations/rearrangements involving CCND1 gene. The evaluation of cyclin D1 expression by immunohistochemistry plays an important role in the diagnostic workup of various hematopoietic diseases. In this review, we aimed to discuss the value of cyclin D1 immunostain in the diagnosis and different diagnosis of hematopoietic neoplasms.

Topics: Cyclin D1; Hematologic Neoplasms; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphocytes; Translocation, Genetic

The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.

Topics: Antineoplastic Agents; Cyclin D1; Everolimus; Hematologic Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Mantle-Cell; Models, Biological; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: beta Catenin; Cyclin D1; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Signal Transduction; Wnt Proteins

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Cycle; Cyclin D1; Cysteine Endopeptidases; Drug Design; Endothelial Growth Factors; Hematologic Neoplasms; Humans; Lymphokines; Multienzyme Complexes; Oligonucleotides, Antisense; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-bcl-2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Long-term exposure to benzene is associated with adverse health effects such as leukemia. Abnormal cell cycle progression has been reported participating in tumorigenesis. Our previous study found that lncRNA-OBFC2A was involved in benzene toxicity through regulating cell proliferation. However, the function of lncRNA-OBFC2A in the regulation of cell cycle remains obscure and the precise mechanisms need to be explored. In vitro study, results showed that benzene metabolic, 1,4-Benzoquinone (1,4-BQ), induced cell cycle arrest at the G1 phase accompanied with decreased expression of Cyclin D1 in a dose-dependently manner. Interestingly, lncRNA-OBFC2A overexpression was found in AHH-1 cells treated with 1,4-BQ and while interference with lncRNA-OBFC2A, the expression of Cyclin D1 were reversed. Further, we found that lncRNA-OBFC2A can interact with Smad3 to control cell cycle via modulating Cyclin D1 expression. In benzene exposed workers, the expression of lncRNA-OBFC2A and Smad3 increased while cyclin D1 decreased which was consistent with the in vitro experiment, meanwhile, the significant associations among them were also found. Thus, these findings indicate that lncRNA-OBFC2A targeted to Smad3 regulated cyclin D1 influences cell cycle arrest induced by 1,4-BQ. LncRNA-OBFC2A, Smad3 and Cyclin D1 as a set of biomarkers play important roles in benzene haematotoxicity.

Topics: Benzoquinones; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin D1; Dose-Response Relationship, Drug; G1 Phase; Hematologic Diseases; Hematologic Neoplasms; Humans; Proteomics; RNA, Long Noncoding; Smad3 Protein

We developed a real-time, quantitative, reverse transcription PCR assay for cyclin D1 (CCND1) expression to aid in the diagnosis of mantle cell lymphoma (MCL). The diagnosis of MCL can be problematic, and existing CCND1 expression assays show a lack of specificity, with elevated expression also detected in other lymphoproliferative disorders. We postulated that evaluating CCND1 expression relative to CCND3 expression by quantitative PCR could offer an improved specificity over an evaluation of CCND1 alone. This method quantitates both CCND1 and CCND3, each normalized to a housekeeping gene (GADPH), using the 5'-exonuclease technique. We analyzed 107 clinical specimens: MCL (17), chronic lymphocytic leukemias (CLL) (10), other non-MCL hematolymphoid disorders (41), non-malignant tissues with an epithelial component (7) and other normal samples (32). This method correctly identified 16 of 17 MCLs, and there were no false positives among any of the other diagnostic groups tested including CLL. CLL presents the major diagnostic dilemma at this institution when diagnosing MCL. Sensitivity studies showed that this method could detect an elevated CCND1/CCND3 ratio when the tumor infiltrate is at least 10% of the cells. We compared the specificity of CCND1 expression alone against the CCND1/CCND3 ratio to demonstrate the increased specificity for the latter. We conclude that the CCND1/CCND3 ratio is a sensitive and specific test for the diagnosis of MCL.

Topics: Cyclin D1; Cyclin D3; Cyclins; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoproliferative Disorders; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity

Three D-type cyclins, cyclin D1, D2 and D3, belong to the G1 cyclin, which regulates the G1/S transition of the cell cycle, and feature highly homologous amino acid sequences. The cyclin D1 gene was found to be transcriptionally activated in B-lymphoid malignancies with t(11;14), but available information is limited regarding expression of cyclin D2 and D3 in hematopoietic malignancies. We examined the expressions of three D-type cyclins to investigate how these homologous genes are differentially used. Northern blot hybridization with densitometric analyses was performed to examine 64 cell lines and 159 patients with various hematopoietic malignancies. Among lymphoid malignancies, cyclin D1 overexpression was exclusively detected in B cell malignancies accompanied by a genetic event consisting of 11q13 chromosomal translocation, consisting of 13 of 19 (68%) patients with mantle cell lymphoma, two of 11 (18%) with B-chronic lymphocytic leukemia, and one of six (17%) with multiple myeloma. The cyclin D2 expression was significantly higher in T cell malignancies than in B cell malignancies (P = 0.003 for cell lines and P < 0.0001 for patient samples, respectively). In the T cell malignancies, cyclin D2 overexpression was predominantly recognized in those with mature phenotype. Furthermore, cyclin D2 expression was upregulated by phytohemagglutinin (PHA) stimulation of normal T-lymphocytes, suggesting that this simply represents the proliferation status of mature T cells. Although cyclin D3 was ubiquitously expressed, its expression was reduced in lymphoid malignancies with cyclin D1 or D2 overexpression. In myeloid leukemias, although three D-type type cyclins were differentially expressed, no preference for particular D-type cyclins was found. This selective usage of D-type cyclins in lymphoid malignancies suggests an existence of a regulatory mechanism among three D-type cyclins.

Topics: Cell Lineage; Cyclin D1; Cyclin D2; Cyclin D3; Cyclins; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Lymphocytes; Tumor Cells, Cultured

The INK4A/ARF locus yields two tumor suppressors, p16INK4A and p14ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone marrow and lymph nodes expressed little or undetectable p16INK4A and p14ARF mRNAs, which were readily detected in 12 and 17 of 41 cell lines, respectively. Patients with hematological malignancies frequently lacked p16INK4A expression (60/137) and lost p14ARF expression less frequently (19/137, 13.9%). Almost all patients without p14ARF expression lacked p16INK4A expression, which may correspond to deletions of the INK4A/ARF locus. Undetectable p16INK4A expression with p14ARF expression in 41 patients may correspond to p16INK4A promoter methylation or to normal expression status of the p16INK4A gene. All patients with follicular lymphoma (FL), myeloma or acute myeloid leukemia (AML) expressed p14ARF while nine of 23 patients with diffuse large B cell lymphoma (DLBCL) lost p14ARF expression. Patients with ALL, AML or blast crisis of chronic myelogenous leukemia expressed abundant p16INK4A mRNAs more frequently than patients with other diseases (12/33 vs 6/104, P < 0.01). Patients with FL and high p14ARF expression had a significantly shorter survival time while survival for patients with DLBCL and increased p14ARF expression tended to be longer. These observations indicate that p16INK4A and p14ARF expression is differentially affected among hemato- logical malignancies and that not only inactivation but also increased expression may have clinical significance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Cyclin D1; DNA Methylation; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, p16; Hematologic Neoplasms; Humans; Lymph Nodes; Lymphoma, Follicular; Male; Middle Aged; Prognosis; Proteins; Retinoblastoma Protein; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Tumor Suppressor Protein p14ARF