Junru Liu

Differentiation induction enhances bortezomib efficacy and overcomes drug resistance in multiple myeloma.

AIM It is of clinical importance to find methods to overcome bortezomib resistance. In the current study, we clarified the relationship between resistance to bortezomib and the differentiation status of myeloma cells, and explored the feasibility of induction of differentiation in overcoming bortezomib resistance in myeloma. METHODS Cell morphology, immunoglobulin light-chain protein secretion levels, and XBP-1 expression were used to evaluate the differentiation status of myeloma cells. Low dose 2-ME2 alone or in combination with ATRA was used to induce differentiation in myeloma cells. RESULTS The differentiation status of myeloma cells was related to myeloma sensitivity to bortezomib. After successful induction of differentiation, the myeloma cells were more sensitive to bortezomib with decreased growth and an increased rate of apoptosis. Induction of differentiation increased the proteasome workload in myeloma cells by increasing immunoglobulin secretion, while reducing proteasome capacity by decreasing proteasome activity. The imbalance between increased proteasome workload and decreased proteasome capacity is a possible mechanism by which induction of differentiation overcomes myeloma resistance to bortezomib. CONCLUSION The current study demonstrated, for the first time, that myeloma differentiation status is associated with myeloma sensitivity to bortezomib and that induction of differentiation can overcome myeloma resistance to bortezomib.

Hepatitis B virus reactivation in patients with multiple myeloma receiving bortezomib-containing regimens followed by autologous stem cell transplant.

Abstract To investigate hepatitis B virus (HBV) reactivation and survival in patients with multiple myeloma (MM) receiving bortezomib-containing regimens, we analyzed 139 patients with MM receiving bortezomib-containing regimens in our hospital. Twenty-seven/139 patients were hepatitis B surface antigen positive (HBsAg+) with nine having DNA levels > 500 IU/mL, including four > 1000 IU/mL. All but five HBsAg+ patients were treated with lamivudine or entecavir before chemotherapy until at least 6 months after chemotherapy or autologous stem cell transplant (ASCT). HBV reactivation occurred in six HBsAg+ patients and two HBsAg− patients, including six who received ASCT. Overall survival and progression-free survival of HBsAg− patients were significantly longer than for HBsAg+ patients (both p < 0.01). From these results, we confirmed that the incidence of HBV reactivation was notable in patients with MM receiving bortezomib-containing regimens, especially those who underwent ASCT. HBsAg+ patients with MM had a poorer prognosis than HBsAg− patients. Prophylactic treatment should be prescribed to all patients with HBsAg+ MM for a minimum duration of 12 months.

High prevalence of hepatitis B virus infection in multiple myeloma

Abstract The aim of the present study was to verify the potential association between multiple myeloma (MM) and hepatitis B/C virus (HBV/HCV) infection. This retrospective case–control trial included 299 patients with MM and 299 patients with acute leukemia (AL). Age and sex were matched between the two groups. The hepatitis B surface antigen (HBsAg) positivity rate was significantly higher in the MM group (19.4% vs. 12.0% in patients with AL; p = 0.014). The rate of HCV infection did not differ between the two groups. The incidence of cirrhosis was significantly higher in HBsAg+ patients (17.2% vs. 6.2% in HBsAg− patients; p = 0.011). The rate of hepatitis E virus (HEV) infection was also significantly higher in HBsAg+ patients (5.2% vs. 0.4% in HBsAg− patients; p = 0.025). Hepatic damage was much more common in HBsAg+ patients than in HBsAg− patients both prior to (22.4% vs. 8.7%; p = 0.006) and during chemotherapy for MM (67.2% vs. 28.6%; p < 0.001). ISS stage, HBsAg+, the use of bortezomib and thalidomide and autologous stem cell transplant were significant factors for overall survival in univariate analysis. In the Cox regression analysis, ISS stage (p = 0.027), HBsAg+ (p = 0.042) and the use of thalidomide (p = 0.001) showed a significant effect on the OS of these patients. The prevalence of HBV infection is higher in patients with MM than in subjects with other hematological malignancies such as AL. Hepatic injury is more common in patients with MM with HBV infection, particularly during chemotherapeutic treatment. HBsAg positivity may be a prognosis factor in patients with MM in HBV endemic areas.

Efficacy and side-effects of decitabine in treatment of atypical chronic myeloid leukemia

Atypical chronic myeloid leukemia (aCML) is a rare and heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, in contrast to chronic myelo...

Detection of erythrocytes in patients with Waldenström macroglobulinemia using atomic force microscopy

The pathological changes of erythrocytes are detected at the nanometer scale, which is important for revealing the onset of diseases and diagnosis. The aim of this study is to examine the ultrastructural changes of erythrocytes in Waldenström macroglobulinemia (WM) at a nanometer scale. Blood samples were collected from two healthy volunteers, two WM patients, and three multiple myeloma (MM) patients when they were first diagnosed. The changes of morphology in the erythrocytes were studied at the nanometer level by high-resolution atomic force microscopy imaging (AFM). Compared with the healthy controls and the MM patients, there were dramatic deformations in the overall shape and surface membrane of the erythrocytes in WM patients. Healthy, pathological WM, and MM erythrocytes could be distinguished by several morphological parameters, including the width, length, length-to-width ratio, valley, peak, peak-to-valley, and Ra. AFM is able to detect the morphological differences in the red blood cells from WM patients, healthy controls, and MM patients. Therefore, the erythrocyte morphology is an important parameter for the diagnosis of WM, which can be used to distinguish WM from MM. The changes of ultrastructure in red blood cells may provide a clue to reveal the mechanism of WM.

Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins

Bendamustine is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers. We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines (RPMI8226 and MM1.S) and primary MM cells. Our results demonstrated a synergistic effect of these drugs, which was effective for both p53-wild-type and p-53-deleted MM cells, but was minimal in mononuclear cells from a healthy donor. Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin-V/PI staining, caspase-3 degradation, and PARP cleavage. Cell death was associated with the up-regulation of the pro-apoptotic protein Bax and the down-regulation of the anti-apoptotic proteins Mcl-1 and survivin. The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the mTOR pathway, p70s6k, and 4EBP-1, as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1.S cells. p21 was also down-regulated upon treatment with the two drugs, suggesting a mechanism of sensitization through the release of cell cycle arrest. Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine, and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and mTOR inhibitors in future clinical practice.

Successful treatment of renal light chain (AL) amyloidosis with bortezomib and dexamethasone (VD).

OBJECTIVE To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with renal light chain (AL) amyloidosis. METHODS Twelve newly diagnosed patients with renal AL amyloidosis were treated with a combination of bortezomib (1.3mg/m(2)/d iv, d1, 4, 8, 11) and dexamethasone (20mg/d iv drip, d1-4). RESULTS Median follow-up time was 22.5 months (range, 2.1-53.6). Ten patients were evaluable. Five out of 10 (50%) patients achieved complete hematologic responses (CHR), and totally 8/10 (80%) achieved hematologic responses (HR). Median time to hematologic response was 1 month. All patients who received HR had no hematologic progression during follow-up period. Five patients (50%) had kidney responses and the other 5 patients (50%) were stable. Median time to kidney response was 3 months. No patients presented renal progression during follow-up. One patient achieved PR after 4 cycles of VD and then received autologous peripheral blood stem cell transplantation. Two out of 10 evaluable patients without hematologic response had died with median overall survival of 8.2 months. Eight of them who had HR were alive with median follow-up time of 28.5 months. Infection (6/12) and fatigue (5/12) were the most frequent side effects. Three patients developed herpes zoster and had to discontinue therapy. CONCLUSIONS VD produces rapid, deep and durable hematological responses and renal responses in the majority of patients with newly diagnosed renal AL. It is well tolerated. This treatment may be a good option as first-line treatment for renal AL amyloidosis patients.

Microarray analysis of an synthetic α-synuclein induced cellular model reveals the expression profile of long non-coding RNA in Parkinson’s disease

Long non-coding RNAs (lncRNAs) are a new research focus that are reported to influence the pathogenetic process of neurodegenerative disorders. To uncover new disease-associated genes and their relevant mechanisms, we carried out a gene microarray analysis based on a Parkinsons disease (PD) in vitro model induced by α-synuclein oligomers. This cellular model induced by 25 μmol/L α-synuclein oligomers has been confirmed to show the stable, transmissible neurotoxicity of α-synuclein, a typical PD pathological marker. And several differentially expressed lncRNAs and mRNAs were identified in this model, such as G046036, G030771, AC009365.4, RPS14P3, CTB-11I22.1, and G007549. Subsequent ceRNA analysis determined the potential relationships between these lncRNAs and their associated mRNAs and microRNAs. The results of the present study widen our horizon of PD susceptibility genes and provide new pathways towards efficient diagnostic biomarkers and therapeutic targets for PD.

Reduced response of IRE1α/Xbp-1 signaling pathway to bortezomib contributes to drug resistance in multiple myeloma cells.

Purpose Proteasome inhibition with bortezomib eliminates multiple myeloma (MM) cells by partly disrupting unfolded protein response (UPR). However, the development of drug resistance limits its utility and resistance mechanism remains controversial. We aimed to investigate the role of IRE1α/Xbp-1 mediated branch of the UPR in bortezomib resistance. Methods The expression level of Xbp-1s was measured in 4 MM cell lines and correlated with sensitivity to bortezomib. LP1 and MY5 cells with different Xbp-1s level were treated with bortezomib; then pivotal UPR regulators were compared by immunoblotting. RPMI 8226 cells were transfected with plasmid pEX4-Xbp-1s and exposed to bortezomib; then apoptosis was determined by immunoblotting and flow cytometry. Bortezomib-resistant myeloma cells JJN3.BR were developed and the effect on UPR signaling pathway was determined. Results By analyzing 4 MM cell lines, we found little correlation between Xbp-1s basic level and bortezomib sensitivity. Bortezomib induced endoplasmic reticulum stress-initiated apoptosis via inhibiting IRE1α/Xbp-1 pathway regardless of Xbp-1s basic level. Exogenous Xbp-1s reduced cellular sensitivity to bortezomib, suggesting the change of Xbp-1s expression, not its basic level, is a potential marker of response to bortezomib in MM cells. Furthermore, sustained activation of IRE1α/Xbp-1 signaling pathway in JJN3.BR cells was identified. Conclusions Our data indicate that reduced response of IRE1α/Xbp-1 signaling pathway to bortezomib may contribute to drug resistance in myeloma cells.

Prognostic value of lactate dehydrogenase in Chinese patients with newly diagnosed transplant eligible multiple myeloma

Beihui Huang , Jin Lu , Xiaotao Wang, Yang Xiao, Ying Zhao, Hongming Huang, Junru Liu, Meilan Chen, Jingli Gu, Shiwen Yuan, Dong Zheng, Yonghua Li, Xiaojun Huang and Juan Li Department of Hematology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Hematology, Peking University Institute of Hematology, Peking University People’s Hospital, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Department of Hematology, Guilin Medical College, Guilin, China; Department of Hematology, The General Hospital of Guangzhou Military Command of PLA, Guangzhou, China; Department of Hematology, The First People’s Hospital of Foshan, Foshan, China; Department of Hematology, Affiliated Hospital of Nantong University, Nantong, China