Weixin Wang

MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response

Background MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma. Design and Methods MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets. Results The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty-four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, -30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502-3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively. Conclusions Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival.

Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications

A novel, genetic immunodeficiency syndrome has been recently described, herein termed “MonoMAC”. It is characterized by severe circulating monocytopenia, NK- and B-lymphocytopenia, severe infections with M. avium complex (MAC), and risk of progression to myelodysplasia/acute myelogenous leukemia. Detailed bone marrow analyses performed on 18 patients further define this disorder. The majority of patients had hypocellular marrows with reticulin fibrosis and multilineage dysplasia affecting the myeloid (72%), erythroid (83%) and megakaryocytic (100%) lineages. Cytogenetic abnormalities were present in 10 of 17 (59%). Despite B-lymphocytopenia, plasma cells were present but were abnormal (e.g. CD56+) in nearly half of cases. Increased T-cell large granular lymphocyte populations were present in 28% of patients. Chromosomal breakage studies, cell cycle checkpoint functions, and sequencing of TERT and K-RAS genes revealed no abnormalities. MonoMAC appears to be a unique, inherited syndrome of bone marrow failure. We describe distinctive bone marrow features to help in its recognition and diagnosis. (Clinicaltrials.gov identifiers: NCT00018044, NCT00923364, NCT01212055)

Aberrant Levels of miRNAs in Bone Marrow Microenvironment and Peripheral Blood of Myeloma Patients and Disease Progression

The bone marrow (BM) microenvironment of multiple myeloma (MM) is reported to play a role in the biology of disease. In this study, we found that the extracellular BM microenvironment in MM contains a unique miRNA signature detectable by miRNA microarray and quantitative real-time PCR, which is partially represented in the peripheral blood. Eleven miRNAs were significantly decreased in both BM and serum of MM patients in comparison with controls. Evaluation of these miRNAs in plasma of a separate cohort of MM patients and controls confirmed significantly aberrant levels of let-7a, let-7b, let-7i, miR-15b, miR-16, and miR-20a in both serum and plasma. We then studied the myeloma precursor diseases and found that a subset of the MM miRNAs exhibited aberrant expression in monoclonal gammopathy of undetermined significance and smoldering myeloma. miRNA analysis of enriched CD138(+) plasma cells from MM and monoclonal gammopathy of undetermined significance found that most of the validated MM BM signature miRNAs were significantly decreased in MM plasma cells. Gene expression profiling indicated that multiple targets of the decreased miRNAs found increased expression in MM plasma cells, including ATF2, HRAS, HDAC4, TGFB1, TGFBR1, and mitogen-activated protein kinases. The findings suggest that these miRNAs are detectable in aberrant levels in the peripheral blood of patients with plasma cell proliferation and may play a role in aberrant plasma cell proliferation and disease progression.

Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease

Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls→SMM→MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment.

Acquired and germline predisposition to bone marrow failure: Diagnostic features and clinical implications

Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias. Although many are associated with characteristic clinical features, recent advances have shown a more complicated picture with a spectrum of broad and overlapping phenotypes and imperfect genotype-phenotype correlations. Distinguishing acquired from inherited forms of marrow failure can be challenging, but is of crucial importance given differences in the risk of disease progression to myelodysplastic syndrome, acute myeloid leukemia, and other malignancies, as well as the potential to genetically screen relatives and select the appropriate donor if hematopoietic stem cell transplantation becomes necessary. Flow cytometry patterns in combination with morphology, cytogenetics, and history can help differentiate several diagnostic marrow failure and/or insufficiency entities and guide genetic testing. Herein we review several overlapping acquired marrow failure entities including aplastic anemia, hypoplastic myelodysplasia, and large granular lymphocyte disorders; and several bone marrow disorders with germline predisposition, including GATA2 deficiency, CTLA4 haploinsufficiency, dyskeratosis congenita and/or telomeropathies, Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia, and Diamond-Blackfan anemia with a focus on advances related to pathophysiology, diagnosis, and management.

Donor-derived MDS/AML in families with germline GATA2 mutation.

TO THE EDITOR: GATA2 encodes a zinc-finger transcription factor that is required for proliferation and survival of hematopoietic stem cells.[1][1] First described in 2011, germline heterozygous mutations in GATA2 lead to haploinsufficiency[2][2] and are associated with bone marrow failure,

Abstract 802: Cytokine profiles in bone marrow supernatant and peripheral blood of patients with multiple myeloma and Waldenström's macroglobulinemia

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Cytokines serve vital roles in the regulation of immune responses. In patients diagnosed with hematologic malignancies, cytokines may play a role in the tumor-host microenvironment affecting tumor survival and progression. Previous studies have quantified the variation in cytokine concentrations between malignant and normal states in patients’ serum. However the research is sparser in relation to measurement of cytokine concentrations in the bone marrow microenvironment. Multiple myeloma (MM) and Waldenstroms macroglobulinemia (WM) are two such malignancies that arise in the B-lymphoid lineage and proliferate within the bone marrow (BM) microenvironment. In this study, an ultra-sensitive IL-6 and a human TH1/TH2 multiplex ELISA system were utilized to determine protein concentrations of the following cytokines: IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p70, IL-13, IFN-gamma, and TNF-alpha, in the BM supernatant and peripheral blood (PB) of 20 patients with WM, 16 patients with MM, and 7 controls. The BM supernatant concentration of TNF-alpha was significantly increased in MM compared to controls (10.650 pg/ml vs. 4.980 pg/ml, p=0.0158). IL-1beta was significantly decreased in the bone marrow supernatant of MM (0.038 pg/ml vs. 2.352 pg/ml, p=0.0469) and WM (0.046 pg/ml vs. 2.352 pg/ml, p=0.0435). IL-8 was also significantly decreased in the BM supernatant of patients with MM (11.520 pg/ml vs. 43.590 pg/ml, p=0.0158) and WM (7.348 pg/ml vs. 43.590 pg/ml, p=0.0036). Differences in BM supernatant concentrations of IL-6 were not significant in MM, WM, and normal controls. Analysis of PB showed IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-alpha were significantly increased in both MM and WM versus controls, and IFN-gamma was significantly increased in WM. Hierarchical clustering analysis of the cytokine profiles suggested two distinct subgroups existed within both MM and WM. TNF-alpha was the only cytokine in our study that was increased in both the bone marrow and serum of MM patients. The discordant results obtained in the BM supernatant vs. PB for IL-6 and IL-8 in both MM and WM indicate that cytokine profiles vary somewhat between the PB and BM compartments. The BM supernatant and PB cytokine profiles in patients with MM and WM highlight the important role cytokines may play in the microenvironment and biology of MM and WM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2011-802