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Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell neoplasm with hepatitis virus supposed to involve in the pathogenesis. The characteristics of SMZL derived from Caucasia population and high hepatitis C virus (HCV) infection region have been widely investigated, but few was reported in the Eastern population with HBV prevalent region. We analyzed the clinical characteristics, cytogenetic aberrations and prognostic factors in 160 SMZL patients from China. 25 patients (16%) were HBsAg-positive and 54 (34%) patients with resolved HBV infection. IGH gene usage was analyzed in 39 patients. The preferential usages of IGHV genes were IGHV1-2 (26%), followed by IGHV4-34 (18%) and IGHV2-70 (10%). The patients with HBV infection presented biased IGHV-D-J rearrangements and mutational status. Using three independent factors hemoglobin level, HBsAg positivity and complex karyotype, we developed a new hierarchical prognostic model, which showed a better c-index than the previously reported IIL and HPLL scoring systems in SMZL. In conclusion, SMZL in HBV prevalent region have unique clinical and biological characteristics and new prognostic scoring model should be adopted in this population.

Multiple myeloma (MM) originates from malignant plasma cells, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs have been reported to be involved in development of bone lesions in MM. However, the circulating microRNA as diagnostic and prognostic biomarkers for bone lesions has not been elucidated yet. In this study, we identified differentially expressed miRNAs that are potentially involved in myeloma-related bone disease in serum of MM patients. MiR-214 and miR-135b was shown to be increased in serum of MM patients with bone lesions. Serum level of miR-214 and miR-135b was highly correlated with the severity of lytic bone lesions and demonstrated as a diagnostic tool for identifying bone diseases based on results of a receiver operating characteristic analysis (ROC). In addition, patients with high levels of serum miR-214 had a dismal survival with significantly shortened progression free survival (PFS) and overall survival (OS). Interestingly, bisphosphonates treatment significantly extended PFS and OS in patients with higher level of miR-214 comparing to patients without bisphosphonates treatment. Taken together, our findings revealed the significance of circulating miR-214 and miR-135b levels in detection of bone disease and in prediction of prognosis of patients with multiple myeloma, suggesting its potential clinical applications. The result of this study also set the foundation for searching more circulating miRNA as biomarker for tumor bone lesions.

MiRNA-15a/16-1 cluster located at chromosome 13q14 has been confirmed to regulate critical genes associated with cell proliferation, apoptosis and drug resistance in multiple myeloma (MM). However, little is known about their expression pattern and prognostic value in MM patients. In this study, we have analyzed the expression levels of miR-15a/16-1 in 117 MM patients (90 newly diagnosed, 11 relapsed and 16 remission patients) and 19 health donors (HDs) by quantitative real-time PCR. Our results indicated that the expression levels of miR-15a and 16-1 were down-regulated in newly diagnosed MM patients as compared to HDs (P = 0.025; P < 0.001) and independent of del(13q14). Downregulation of miR-15a was significantly associated with disease progression and poor prognosis while miR-16-1 seemed to be a good diagnostic marker to distinguish MM from HDs with area under the curve (AUC) of 0.864, sensitivity of 100% and specificity of 73%. Furthermore, patients with miR-15a < 2.35 (low expression group) had significantly shorter PFS (P < 0.001) and OS (P < 0.001). After adjustment of the established prognostic variables including del(13q), del(17p), amp(1q21) and high risk genetic abnormality, low miR-15a expression (

Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical characteristics and outcomes. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MM patients. In the present study, MLPA analysis was applied to analyze cytogenetics of CD138 tumor cells of 59 MM samples, and its result was compared, retrospectively, with the interphase fluorescence in situ hybridization (iFISH) data. We firstly established the normal range of each of the 42 diagnostic probes using healthy donor samples. A total of 151 aberrations were detected in 59 patient samples, and 49/59 cases (83.1%) harbored at least one copy number variation. Overall, 0-7 aberrations were detected per case using MLPA, indicating the heterogeneity and complexity of MM cytogenetics. We showed the high efficiency of MLPA and the high congruency of the two methods to assess cytogenetic aberrations. Considering that MLPA analysis is not reliable when the aberration only exits in a small population of tumor cells, it is essential to use both MLPA and iFISH as complementary techniques for the diagnosis of MM.

// Fei Li 1, 2 , Yan Xu 1 , Ping Deng 4 , Ye Yang 5 , Weiwei Sui 1 , Fengyan Jin 6 , Mu Hao 1 , Zengjun Li 1 , Meirong Zang 1 , Dehui Zhou 1 , Zhimin Gu 5 , Kun Ru 1 , Jianxiang Wang 1 , Tao Cheng 1 , Lugui Qiu 1, 3 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China 2 Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China 3 Umbilical Cord Blood Bank of Tianjin, Tianjin 300020, China 4 Department of Science and Education, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China 5 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52246, USA 6 Tumor Center, The First Hospital of Jilin University, Changchun 130021, China Correspondence to: Lugui Qiu, e-mail: drqiu99@medmail.com.cn Keywords: 12p13 deletion, CD27 gene, prognosis, bortezomib, multiple myeloma Received: January 09, 2015 Accepted: February 08, 2015 Published: March 20, 2015 ABSTRACT The deletion of 12p (del(12p)) has been described as a novel negative prognostic marker in multiple myeloma (MM) and has gained increasing attention in recent years. However, its impact on MM is still controversial. In this study, we comprehensively evaluated the clinical impact of 12p13 deletion using fluorescence in situ hybridization (FISH) on 275 newly diagnosed MM cases treated in a prospective, non-randomized clinical trial (BDH 2008/02). The results showed that deletion of 12p13 was detected in 10.5% of newly diagnosed cases and associated with multiple indicators for high tumor burden including ISS III, BM plasmacytosis larger than 50%, and renal lesion. Moreover, the cases with 12p13 deletion typically had higher incidence of del(17p), IGH translocation and t(4;14). Patients with del(12p) conferred significantly adverse prognosis for PFS and OS, even in patients subjected to bortezomib-based therapy. When adjusted to the established prognostic variables including del(13q), del(17p), t(4;14), amp(1q21), ISS stage and LDH, del(12p13) remained the powerful independent adverse factor for PFS ( P = 0.007) and OS ( P = 0.032). In addition, del(12p13) combined with high β2-MG, high LDH and bone lesion can further identify subpopulations with high-risk features. Our results strongly supported that del(12p13) can be used as a valuable prognostic marker in MM.

B-cell chronic lymphoproliferative disorders (B-CLPD) comprise several entities with indolent clinical manifestations but heterogeneous survival. Cytogenetic aberrations are now the standard prognostic predictors in chronic lymphocytic leukemia (CLL) but have been less investigated in other subtypes of B-CLPD. In this study, we detected cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 875 B-CLPD patients, based on a panel probes locating at 13q14, 11q22, 17p13 and CEP12. We identified del17p acted as the independent adverse cytogenetic predictor for overall survival (OS) in CLL. Del13q, del11q and del17p were adverse factors for OS in Waldenstrom's macroglobulinemia in the univariate analysis but lost their role in the multivariate analysis. Trisomy 12 acted as an independent poor factor for both marginal zone lymphoma (MZL) and unclassified B-CLPD (BCLPD-U) subtype. Del17p did not impact survival in MZL and BCLPD-U patients. These contrasting results indicate different roles of the same cytogenetic aberrations in the pathogenesis of each B-CLPD subtype. As del17p contributed to the poorest survival in CLL and desired extraordinary treatment strategy, the imitation of CLL strategy to other B-CLPD with del17p should be carefully advocated based on this study.

The incidence and prognostic role of MYC and BCL2 rearrangements in mature B-cell lymphomas have been extensively studied, except the infrequent mantle cell lymphoma (MCL). Here, we analyzed the MYC and BCL2 abnormalities and other cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 50 MCL patients with bone marrow involvement. Eighteen patients (36.0%) had MYC gains and/or amplifications, and twelve patients (24.0%) had BCL2 gains and/or amplifications. Among the 18 patients with MYC abnormality, four had simultaneous MYC translocations, but no BCL2 translocation was detected among patients with BCL2 abnormality. Only two patients (4.0%) had both MYC and BCL2 abnormalities. The patients with a MYC abnormality had a significantly higher tumor burden, a higher percentage of medium/high risk MIPI group and genomic instability compared to those without this abnormality. However, no significant difference was observed between patients with or without a BCL2 abnormality in terms of clinical and cytogenetic factors. Patients with a MYC abnormality had poorer progress-free survival (PFS) (9.0 vs. 48.0 months, p = .000) and overall survival (OS) (12.0 vs. 94.5 months, p = .000), but the presence of a BCL2 abnormality did not significantly influence either PFS or OS. In multivariate analysis, the MYC abnormality was the independent adverse factor for both PFS and OS, and intensive chemotherapy did not improve the outcome of these patients. Thus, the presence of a MYC but not BCL2 abnormality predicted the poor survival of MCL patients, and a new treatment strategy should be developed for these patients.