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Selective BCL2 inhibitor ABT-199 has been approved to treat hematological malignancies including acute myeloid leukemia (AML). However, acquired drug resistance and severe side effects occur after extended treatment limiting the clinical usage of ABT-199. Here, we successfully encapsulated pure ABT-199 in amphiphilic mPEG-b-PTMC

Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as “smoldering MCL” (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.

Background Iron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism. Methods We established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload. Results Iron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy. Conclusions Our results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.

Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin B-cell lymphoma and therapeutic options of MCL are limited. We conducted a real-world, multicenter study enrolled 1261 MCL patients from nine medical centers in China to evaluate patients’ outcomes.Methods: This retrospective study enrolled 1261 adult MCL patients between January 2000 and December 2020 from nine medical centers in China. Patients’ characteristics, treatment and survival outcomes were evaluated. Results:145 patients (11%) received Bruton’s tyrosine kinase inhibitors (BTKi)-containing regimens as frontline therapy. 12% of the younger patients received autologous hematopoietic stem cell transplantation (AHCT) consolidation. The estimated 2-year progression-free survival (PFS) and 5-year overall survival (OS) rate from the initiation of front-line treatment for the entire cohort was 62.4% and 57.2% respectively. Age≥65 years, high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI), Ki-67>30% and blastoid/pleomorphic histology were associated with shorter PFS or OS. For younger patients, induction therapy with BTKi-containing regimens yield similar efficacy in 3-year PFS and OS as compared to the standard high-dose immunochemotherapy with AHCT (65.5% vs 66.6%, p=0.907 and 84.8% vs 92.3%, p=0.204). For the relapsed or refractory MCL patients in this cohort, the 5-year OS from the initiation of salvage therapy was 36.0%. A total of 23 patients developed hepatitis B virus (HBV) reactivation after immunochemotherapy, while BTKi treatment was not associated with higher rate of HBV reactivation. Conclusions:In conclusion, for younger Chinese MCL patients, the addition of BTKi in frontline therapy is a safer and more convenient alternative treatment strategy. For MCL patients with resolved hepatitis B, anti-HBV prophylaxis should not be neglected.

Despite significant efficacy of ibrutinib therapy in mantle cell lymphoma (MCL), about one-third of MCL patients will display primary resistance. In time, secondary resistance occurs almost universally with an unlikely response to salvage chemotherapy afterwards. While intense efforts are being directed towards the characterization of resistance mechanisms, our focus is on identifying the signalling network rewiring that characterizes this ibrutinib resistant phenotype. Importantly, intrinsic genetic, epigenetic and tumour microenvironment-initiated mechanisms have all been shown to influence the occurrence of the ibrutinib resistant phenotype. By using in vitro and in vivo models of primary and secondary ibrutinib resistance as well as post-ibrutinib treatment clinical samples, we show that dual targeting of the BCL-2 and PI3-kinase signalling pathways results in synergistic anti-tumour activity. Clinically relevant doses of venetoclax, a BCL-2 inhibitor, in combination with duvelisib, a PI3Kδ/γ dual inhibitor, resulted in significant inhibition of these compensatory pathways and apoptosis induction. Our preclinical results suggest that the combination of venetoclax and duvelisib may be a therapeutic option for MCL patients who experienced ibrutinib failure and merits careful consideration for future clinical trial evaluation.

The association between serum albumin level and clinical outcomes has been reported for several hematological malignancies. Our study aimed to identify the relationship between serum albumin level ...

AML1‐ETO, the most common fusion oncoprotein by t (8;21) in acute myeloid leukaemia (AML), enhances hematopoietic self‐renewal and leukemogenesis. However, currently no specific therapies have been reported for t (8;21) AML patients as AML1‐ETO is still intractable as a pharmacological target. For this purpose, leukaemia cells and AML1‐ETO‐induced murine leukaemia model were used to investigate the degradation of AML1‐ETO by melatonin (MLT), synthesized and secreted by the pineal gland. MLT remarkedly decreased AML1‐ETO protein in leukemic cells. Meanwhile, MLT induced apoptosis, decreased proliferation and reduced colony formation. Furthermore, MLT reduced the expansion of human leukemic cells and extended the overall survival in U937T‐AML1‐ETO‐xenografted NSG mice. Most importantly, MLT reduced the infiltration of leukaemia blasts, decreased the frequency of leukaemia stem cells (LSCs) and prolonged the overall survival in AML1‐ETO‐induced murine leukaemia. Mechanistically, MLT increased the expression of miR‐193a, which inhibited AML1‐ETO expression via targeting its putative binding sites. Furthermore, MLT decreased the expression of β‐catenin, which is required for the self‐renewal of LSC and is the downstream of AML1‐ETO. Thus, MLT presents anti‐self‐renewal of LSC through miR‐193a‐AML1‐ETO‐β‐catenin axis. In conclusion, MLT might be a potential treatment for t (8;21) leukaemia by targeting AML1‐ETO oncoprotein.

Background: Acute myeloid leukemia(AML) is a highly heterogeneous hematological malignancy. Despite, increase in treatment options for AML over the past decade, prognosis for AML remain dismal. Numerous prognostic models have been developed for this disease, however nomograms predicting long-term survival in AML patients after induction chemotherapy(IA regimen) have not been described.Method: We constructed nomograms to predict disease-free survival(DFS) and overall survival(OS) by analyzing the cohort of patients with de novo non-M3 AML patients who underwent induction chemotherapy between June 2008 to August 2019. We utilized univariable and multivariable Cox proportional hazards regression analyses to obtain the selected variables for the nomograms. The discriminative ability and calibration were tested using C statistics, calibration plots, and Kaplan-Meier curves.Results: A total of 360 patients who underwent induction chemotherapy with IA regimen were included in the study. Of these 55% were male with a median age was 48 years. Using the univariate and multivariate analyses, the following variables were identified in the prediction of DFS: age(HR, 1.770; 95%CI, 1.160-2.702; P = 0.008), Hb(HR, 0.634; 95%CI, 0.462-0.870; P = 0.005), albumin(HR, 0.473; 95%CI, 0.363-0.615; P < 0.001) and cyto/molecular risk group(intermediate vs. favorable: HR, 1.614; 95%CI, 1.128-2.309; P = 0.001; poor vs. favorable: HR, 2.459; 95%CI, 1.645-3.676; P < 0.001) at the time of diagnosis, and allo-HSCT treatment(HR, 0.341; 95%CI, 0.234-0.497; P < 0.001). Factors which predicted OS were Hb (HR, 0.616; 95%CI, 0.438-0.866; P = 0.005), albumin (HR, 0.448; 95%CI, 0.340-0.591; P < 0.001), cyto/molecular risk group (intermediate vs. favorable: HR, 1.558; 95%CI, 1.068-2.275; P = 0.021; poor vs. favorable: HR, 2.348; 95%CI, 1.523-3.620; P < 0.001), allo-HSCT treatment (HR, 0.256; 95%CI, 0.166-0.396; P < 0.001), and age (HR, 1.528; 95%CI 0.980-2.382; P = 0.061). The discriminative ability and calibration of the nomograms revealed good predictive ability as indicated by the C statistics (0.715 for DFS and 0.731 for OS). Conclusion: Independent predictors of survival and relapse risk after IA regimen for AML can be utilized to obtain survival nomograms. These nomograms were able to predict DFS and OS while having good calibration accuracy and discriminative ability on internal validation.

Background Overexpression of Wilms’ tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whether WT1 is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood. Methods MLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown of wt1 on the self-renewal ability of LSC. RNA sequencing was performed on WT1-overexpressing cells to select WT1 targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2Rγ (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo. Results We found that wt1 is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression of BCL2L2, a member of B cell lymphoma 2 (BCL2) family, by direct binding to its promoter region. Loss of WT1 impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein. Conclusions Our results indicate that WT1 is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.

The natural history of mantle cell lymphoma (MCL) undergoing chemotherapy is a cyclical pattern of remission followed by recurrence of disease due to acquired chemotherapy resistance. The median age of the occurrence of MCL is 65 years, so half of the newly diagnosed MCL patients are considered “elderly.” The tolerance to long-term chemotherapy in elderly patients is decreased; hence, the response to frontline therapy used is of paramount importance. We hope that our review may guide clinicians in treating such populations in a more personalized and evidence-based manner. In the older patients with risk variables, frontline treatment is determined according to different body status of fit, unfit or compromised, and frail. In the fit patients, the pursuit of remission and prolongation of survival might currently justify the use of more intense and toxic therapies. For unfit or compromised older patients, disease control needs to be prioritized, maintaining a balance between the benefits and toxicities of the treatment. For frail patients, tolerance of treatment and minimizing myelotoxicity should be the primary focus. “Chemotherapy-free” regimens are likely to be considered as the first-line strategy for this population. On the other hand, in the older MCL population without risk variables, observation or “watch and wait” can prevent overtreatment. Furthermore, more clinical trials and research studies on novel agents and targeted therapies need to be translated into the general population to provide optimal treatment and to guide personalized treatment. Implications for Practice This review emphasizes the importance of frontline therapies for older MCL patients. MCL patients commonly experience a cyclical pattern of remission followed by recurrence of disease due to acquired chemotherapy resistance. As a special population, elderly patients have various comorbidities and decreased organ function, which may reduce the chances of undergoing treatment for recurrent disease. Thus, this older population of patients with MCL should be treated separately and exceptionally. So far, systematic reviews with regard to frontline treatment for older patients with MCL have not been encountered, but the hope is that this review may guide clinicians in treating such populations in a more personalized and evidence-based manner.

Gastrointestinal acute graft-vs.-host disease (GI aGVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation and is a major cause of morbidity and mortality. In addition, GI aGVHD is often clinically indistinguishable from other causes of GI dysfunction such as conditioning regimen toxicity, infections, or medications, which complicates the diagnosis. Thus, specific biomarkers are needed to help improve diagnosis and obtain a deeper understanding of the cytokine changes in GI aGVHD. An MHC-mismatched model of aGVHD was established by transplanting 1 × 107 bone marrow nuclear cells and 3 × 107 spleen cells from C57/Bl6 mice or from BALB/c mice into lethally irradiated BALB/c recipients. The mice in the allogeneic transplantation group were intraperitoneally treated with 20 mg kg−1 day−1 cyclosporin A after aGVHD developed. Five micrograms of lipopolysaccharide were administered intraperitoneally daily to syngeneic recipients at day 11 to imitate infection; the same volume of phosphate-buffered saline was administered to control mice. The mice were killed at the indicated time points. Forty molecules derived from the GI tract were screened cytokine array. The data demonstrated that the expression of B lymphocyte chemoattractant (CXCL13) was increased by ~10-, 12-, and 16-fold upon the occurrence of aGVHD compared with infection, aGVHD after treatment, and the syngeneic control group, respectively. Thus, the elevation of BLC (CXCL13) is an indicator of acute GI GVHD.

Background Relapsed or refractory mantle cell lymphoma (MCL) has a poor prognosis. The best outcome is achieved in patients who have a partial or complete response to salvage treatment and proceed to allogeneic stem cell transplant. Patients and Methods Twenty-one patients were given a combination regimen of bortezomib, cyclophosphamide, and rituximab at MD Anderson Cancer Center as part of a single-arm, prospective, open-label phase II clinical trial. The median age was 66 years, with a median number of prior treatments of three. Sixty-seven percent had failed intensive chemoimmunotherapy and 43% were intermediate/high risk according to the MCL international prognostic index score, with a median Ki-67 proliferation index of 45% in those who were tested. Results The rates of overall and complete response achieved were 74% and 42%, respectively, with median progression-free and overall survivals of 9 months and 36.4 months, respectively. The regimen's toxicity profile was acceptable; only 25% of the cycles resulted in grade 3 or 4 neutropenia or thrombocytopenia, and only 3% of cycles produced grade 3–4 fatigue. There were no episodes of grade 3–4 neuropathy. Conclusion The combination of bortezomib with cyclophosphamide and rituximab is an effective and well-tolerated regimen in patients with relapsed/refractory MCL. Because of its low toxicity, future combinations of this regimen with other promising drugs that have different mechanisms of action offer a realistic possibility that may improve outcomes for patients who have MCL.

AML1-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AML1-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration- and time-dependent manner in leukemic cell lines and primary AML blasts with t(8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AML1-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AML1-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein.

Additional file 9: Table S4. Limiting dilution assay of MLL-AF9-induced mouse leukemia treated with or without WP1130.

Additional file 1: Table S1. Clinical characteristics of AML patients.

Additional file 8: Table S3. Limiting dilution assay of MLL-AF9-induced mouse leukemia transduced with sh-nc or sh-wt1.

Additional file 4: Table S2. The sequences of primers for qRT-PCR and construction of plasmids.

Additional file 2: Materials and methods.

The association between serum albumin level and clinical outcomes has been reported for several hematological malignancies. Our study aimed to identify the relationship between serum albumin level at the time of diagnosis and subsequent clinical outcomes in patients with newly diagnosed acute myeloid leukemias (AMLs) other than acute promyelocytic leukemias (APLs). A total of 243 patients with

Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.The proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter regions.CO-IP was used to explore the interaction between Sp1 and p300.The mRNA expression levels of Sp1,p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression; overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression; Sp1 and p300 had a positive regulation effect on IQGAP1.Over expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.

Increased absolute monocyte count (AMC) at presentation has recently been associated with clinical outcome in different types of hematological malignancies. This study aimed to assess the prognostic value of AMC on survival in 193 adult patients with de novo non-M3 acute myeloid leukemia (AML). The median AMC for all patients at diagnosis was 0.26 × 10(9)/L, with 41.4, 31.1 and 27.5% of patients showed low (0.12 × 10(9)/L), normal (0.12-0.80 × 10(9)/L), and high AMC (0.80 × 10(9)/L), respectively. Univariate analysis revealed that high AMC appeared as a poor prognostic factor for overall survival (OS) (p = 0.0055), but not for disease free survival (DFS) (p = 0.1195). On multivariate analysis, initial high AMC remained an independent predictor of OS (hazard ratio 2.01, p = 0.017). Our results suggest that AMC at diagnosis, which provides additional prognostic information independently from conventional factors related to patient clinical characteristics or tumor biological features, could be a novel prognostic marker for AML.

The increasing prevalence of Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae (KPC-2-KP) infections can become a new life-threatening complication for hematological patients. Five cases of KPC-2-KP bloodstream infections have been identified in our hematology department over the past 10 years. The current treatment options do not show satisfactory efficacy, especially for bloodstream infections. The treatment of these five cases was unsuccessful, mainly due to the high minimum inhibitory concentrations of carbapenem, fosfomycin resistance, or the inaccessibility of polymyxin. Further investigations into the optimal treatment modalities are therefore imperative. The present study provides insights into the epidemiology and clinical challenges of treating KPC-2-KP bloodstream infections.

The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL.

aGVHD was verified by histological changes in allogeneic recipients. (A and B) Donor-derived cells in the allogeneic group were measured by flow cytometry at day 7 to confirm implantation of donor. (C) H&E staining of mouse small intestine tissues in the allogeneic group on day 7. Small intestinal mucous villi degenerate and denude. (D) H&E staining of mouse small intestinal tissues of mice in the syngeneic group on day 7. Small intestinal mucosa had no obvious pathological changes. n=5 mice per time point per group. (DOC 3783 kb)

Positive iTRAQ label of proteins with increased levels in day 7 in allogeneic group with aGVHD.8-plex iTRAQ approach is that the relative quantification is achieved via the difference in abundance of the reporter product ions (i.e., m/z 113, 114, 115, 116, 117, 118, 119, 121). For positive labeling, 115 was day 0, 114 was day 3 (allogeneic group), 116 was day 7 (syngeneic group), 117 was day 7 (allogeneic group), 118 was day 11(syngeneic group ip PBS), 119 was day 11 (syngeneic group ip LPS), and 121 was day 15 (after CsA treatment in allogeneic group), 113 was labeled day 22 (syngeneic group). Differential protein levels between aGVHD+ and aGVHD- from eight time points were evaluated for 117/115, 117/114, 117/116, 117/121, 117/118, 117/119 and 117/113 sets, respectively, with the ratio more than 2.0 defined as increased. (DOC 48 kb)

Background Spontaneous regression has been reported in some indolent forms of lymphoma. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm and has a poor prognosis. However, approximately 30% of MCL patients can exhibit indolent clinical behavior. To date, complete spontaneous regression of MCL has not been reported. Case presentation We describe four cases of spontaneous regression of MCL. At the time of presentation, these patients were asymptomatic, with lymph node enlargement and mild to moderate fluorodeoxyglucose (FDG) uptake on FDG-positron emission tomography combined with computed tomography. One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity, which may have a role in the clearance of tumor cells. Conclusions In this report, we support the use of a “wait and watch” strategy for MCL patients with no risk factors and indolent behavior. This strategy helps spare patients from further potentially harmful chemotherapy. In addition, we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.

Background Gastrointestinal acute graft-versus-host disease (GI aGVHD) is a lethal complication following allogeneic hematopoietic stem cell transplantation (HSCT). However, it is still very difficult to make a diagnosis of GI aGVHD in practice. To date, no consensus plasma biomarker of GI aGVHD can be used to help make a diagnosis. Here, we attempted to identify GI aGVHD associated plasma proteins in murine model, which can help make a diagnosis of GI aGVHD. Methods We used 8-plex isobaric tags for relative and absolute quantitation (8-plex iTRAQ) to screen out proteins in plasma samples taken from murine models before and after allogeneic HSCT. Next mRNA expressions were validated by quantitative real-time polymerase chain reaction in mouse intestinal epithelial samples. Results We found that five proteins were increased at least 2-fold in the allogeneic group at day 7 compared with days 0, 3 and 15 (after Cyclosporin A treatment) and the syngeneic group at day 7. These 5 proteins were VNN3, ZNF746, C4BP, KNG1 and FETUB, and they were consistent with results from negative labeling with 8-plex iTRAQ. Furthermore, increase in mRNA level of VNN3 was confirmed in murine intestinal epithelial samples with aGVHD. Conclusions Our results demonstrate that plasma VNN3 protein is associated with GI aGVHD in murine model. Electronic supplementary material The online version of this article (10.1186/s12950-017-0178-z) contains supplementary material, which is available to authorized users.

Honokiol, a constituent of Magnolia officinalis, has been reported to possess potent anti-cancer activity through targeting multiple signaling pathways in numerous malignancies including acute myeloid leukemia (AML). However, the underlying mechanisms remain to be defined. Here, we report that honokiol effectively decreased enzyme activity of histone deacetylases (HDACs) and reduced the protein expression of class I HDACs in leukemic cells. Moreover, treatment with proteasome inhibitor MG132 prevented honokiol-induced degradation of class I HDACs. Importantly, honokiol increased the levels of p21/waf1 and Bax via triggering acetylation of histone in the regions of p21/waf1 and Bax promoter. Honokiol induced apoptosis, decreased activity of HDACs, and significantly inhibited the clonogenic activity of hematopoietic progenitors in bone marrow mononuclear cells from patients with AML. However, honokiol did not decrease the activity of HDACs and induce apoptosis in normal hematopoietic progenitors from unbilicial cord blood. Finally, honokiol dramatically reduced tumorigenicity in a xenograft leukemia model. Collectively, our findings demonstrate that honokiol has anti-leukemia activity through inhibiting HDACs. Thus, being a relative non-toxic agent, honokiol may serve as a novel natural agent for cancer prevention and therapy in leukemia. J. Cell. Biochem. 116: 287–298, 2015. © 2014 Wiley Periodicals, Inc.

The present study was designed to explore the role of IQ motif-containing GTPase activating protein 1 (IQGAP1) in the cell proliferation of multiple myeloma (MM) via the MAP kinase (ERK) pathway. Reverse transcription‑polymerase chain reaction (RT-PCR) and western blot analysis were carried out to evaluate the expression of IQGAP1 in RPMI8226, U266 and KM3 cell lines and in primary MM cells from 4 MM patients. shRNA-expressing plasmids were used in RPMI8226 cells to knock down IQGAP1 and an MTT assay was used to examine the proliferative activity of the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells in subgroups stimulated with VEGF/IL-6 or without. Western blot analyses were then performed to examine the protein levels of p-ERK1/2, ERK1/2, AKT, p-AKT, STAT3, p-STAT3 in the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells. Co-immunoprecipitation was used to verify the interaction between the IQGAP1 scaffold and the MAP ERK kinase. We found that IQGAP1 was overexpressed in the human myeloma cell lines and in the patient MM cells. The proliferation rate in the RPMI8226 cells was decreased when IQGAP1 was knocked down with shRNA. IQGAP1 was found to affect RPMI8226 cell proliferation by regulation of the MAP kinase (ERK1/2) pathway; IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.

The increasing prevalence of Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae (KPC-2-KP) infections can become a new life-threatening complication for hematological patients. Five cases of KPC-2-KP bloodstream infections have been identified in our hematology department over the past 10 years. The current treatment options do not show satisfactory efficacy, especially for bloodstream infections. The treatment of these five cases was unsuccessful, mainly due to the high minimum inhibitory concentrations of carbapenem, fosfomycin resistance, or the inaccessibility of polymyxin. Further investigations into the optimal treatment modalities are therefore imperative. The present study provides insights into the epidemiology and clinical challenges of treating KPC-2-KP bloodstream infections.

Despite the use of novel anti-myeloma agents,nearly all patients will eventually relapse or become refractory to drug treatment. New and more effective drugs for multiple myeloma (MM) are urgently needed. The JAK-STAT signaling pathway is important in the proliferation of myeloma cells.Lycorine,a natural alkaloid extracted from amaryllidaceae, has shown anti-tumor effects against a variety of solid tumors. However, its effects on MM remain unclear.In this study,we found that lycorine inhibited cellular viability and induced cell death in MM cell lines and primary myeloma cells which were derived from our four MM patients. The study showed that myeloma cells' cycle was being arrested under the G0/G1 phase followed by the lycorine treatment. Further mechanism analysis demonstrated that lycorine inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells and patient MM cells.Importantly, we found that knockdown of HDAC8 resulted in increased expression of SOCS1. Collectively, our findings suggested lycorine acted as a potent novel histone deacetylase inhibitor and inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells.

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses to frontline therapy. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK) has achieved a 68% overall response rate in relapsed/refractory MCL patients (Wang et al., NEJM, 2013). However, the vast majority of MCL patients experience disease progression; therefore, novel therapies to overcome ibrutinib resistance are urgently needed. Ibrutinib resistance is associated with the dysregulation of alternative signaling pathways such as the apoptotic pathway and PI3K/AKT signaling; therefore, combinatorial therapeutic strategies may prove fruitful in overcoming ibrutinib resistance via the blockade of these compensatory pathways. Based on the upregulation of the PI3K signaling pathway and the anti-apoptotic pathway in ibrutinib resistance, we co-inhibited both pathways with the dual PI3K-delta and -gamma inhibitor duvelisib and the BCL-2 inhibitor venetoclax to assess the ability of this combination to overcome ibrutinib resistance in MCL. Methods: Cell viability and apoptosis assays were conducted to assess the effects of venetoclax and duvelisib on 4 ibrutinib-resistant cell lines (Jeko BTK KD, Jeko-R, Z-138 and Maver-1) and 4 primary patient samples. We also confirmed the synergistic effect of this combination on two ibrutinib-resistant cell lines (Jeko BTK KD and Z-138) by western blotting. Aberrant protein expression between single agents and drug combination in Jeko BTK KD cells was detected using Reverse Phase Protein Array (RPPA) analysis with confirmation by western blotting. Cell migration of Jeko BTK KD cells was assessed. A Jeko-1 cell xenograft (which is resistant to ibrutinib in vivo) was established in NSG mice, and drug testing was performed in this model with tumor burden assessed viain vivo imaging. Results: We observed synergistic activity with the combination of venetoclax and duvelisib in 4 ibrutinib-resistant cell lines (Jeko BTK KD, 0.36; Jeko-R, 0.47; Z-138, 0.66; Maver-1, 0.41) and in 4 ibrutinib-resistant patient samples (PT1, 0.14; PT2, 0.43; PT3, 0.52; PT4, 0.41) by calculating the synergistic index (Ki value). We confirmed the synergistic effects of this combination by observing apoptosis at 72 hours post-treatment in Jeko BTK KD and Z-138 cells. Moreover, the combination of venetoclax and duvelisib synergistically reduced the cell migration of Jeko BTK KD cells. RPPA analysis of Z-138 MCL cells post-treatment demonstrated that multiple pathways, including the apoptotic pathway as well as the PI3K/AKT and BCR signaling pathways, were synergistically altered by venetoclax and duvelisib. Moreover, venetoclax and duvelisb synergistically reduced tumor burden in a Jeko-1 cell xenograft model resistant to ibrutinib. Conclusion: PI3K signaling and BCL-2-related pathways are activated in ibrutinib-resistant MCL cells, and targeting these pathways using a combinatorial approach may potentially overcome ibrutinib resistance. Disclosures Wang: AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; MoreHealth: Consultancy; Juno: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria.

Plasma is recognized as a promising source of disease-related biomarkers, and proteomic approaches for identifying novel plasma biomarkers are in great demand. However, the complexity and dynamic protein concentration range of plasma remain the main obstacles for current research in this field. In this study, plasma proteins were prefractioned by immunodepletion and Protein Equalizer Technology to remove high abundant proteins, then labeled with an 8-plex isobaric tags for relative and absolute quantitation (iTRAQ) to improve the peptide ionization, and analyzed by strong-cation-exchange(SCX) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our results showed that both prefraction methods were complementary, with regard to the number of identified proteins. Good chromatographic technique is important to further fractionate the iTRAQ labeling peptides, which allowed 320 and 248 different proteins to be characterized from two prefraction methods, respectively, encompassing a wide array of biological functions and a broad dynamic range of 10(7). Furthermore, the accuracy of iTRAQ relative quantitation for differentially expressed proteins is associated with the number of peptides hits per protein.