ABSTRACT
Mantle cell lymphoma (MCL) is an uncommon and incurable B-cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg-negative (HBsAg-) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki-67. The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens. Compared with CHOP, the HD-AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hepatitis B virus , Hepatitis B , Lymphoma, Mantle-Cell , Mutation , Humans , Male , Female , Middle Aged , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/genetics , Aged , Hepatitis B virus/genetics , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatitis B/virology , Hepatitis B/pathology , Aged, 80 and over , Hepatitis B Surface Antigens/blood , Vincristine/therapeutic use , Vincristine/administration & dosage , Cyclophosphamide/therapeutic use , Cyclophosphamide/administration & dosage , Doxorubicin/therapeutic use , Doxorubicin/administration & dosage , Treatment OutcomeABSTRACT
CD47 is a cell-surface ligand that is overexpressed in various malignancies and that binds to SIRPα on macrophages to promote tumor cell evasion of phagocytosis. Blocking the CD47-SIRPα axis can increase the phagocytosis of macrophages to exert antitumor effects. CD47-based immunotherapy is a current research focus. The combination of anti-CD47 antibodies with other drugs has shown encouraging response rates in patients with hematological tumors, but side effects also occur. Bispecific antibodies and SIRPα/Fc fusion proteins appear to balance the efficacy and safety of treatment. We review the latest clinical research advances and discuss the opportunities and challenges associated with CD47-based immunotherapy for hematological malignancies.
Subject(s)
Hematologic Neoplasms , Neoplasms , Humans , CD47 Antigen/metabolism , Phagocytosis , Macrophages , Neoplasms/therapy , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/metabolismABSTRACT
BACKGROUND: miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined. METHODS: To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro. RESULTS: miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation. CONCLUSIONS: Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.
Subject(s)
Antineoplastic Agents , MicroRNAs , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Adult , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , DNA Methylation/genetics , Lymphocytes/metabolism , Mice, Knockout , MicroRNAs/genetics , MicroRNAs/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/therapeutic use , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolismABSTRACT
Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hepatitis B , Lymphoma, Mantle-Cell , Adult , Humans , Aged , Lymphoma, Mantle-Cell/drug therapy , Rituximab/therapeutic use , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols , Cytarabine/therapeutic useABSTRACT
Rationale: microRNAs (miRNAs) are frequently deregulated and play important roles in the pathogenesis and progression of acute myeloid leukemia (AML). miR-182 functions as an onco-miRNA or tumor suppressor miRNA in the context of different cancers. However, whether miR-182 affects the self-renewal of leukemia stem cells (LSCs) and normal hematopoietic stem progenitor cells (HSPCs) is unknown. Methods: Bisulfite sequencing was used to analyze the methylation status at pri-miR-182 promoter. Lineage-negative HSPCs were isolated from miR-182 knockout (182KO) and wild-type (182WT) mice to construct MLL-AF9-transformed AML model. The effects of miR-182 depletion on the overall survival and function of LSC were analyzed in this mouse model in vivo. Results: miR-182-5p (miR-182) expression was lower in AML blasts than normal controls (NCs) with hypermethylation observed at putative pri-miR-182 promoter in AML blasts but unmethylation in NCs. Overexpression of miR-182 inhibited proliferation, reduced colony formation, and induced apoptosis in leukemic cells. In addition, depletion of miR-182 accelerated the development and shortened the overall survival (OS) in MLL-AF9-transformed murine AML through increasing LSC frequency and self-renewal ability. Consistently, overexpression of miR-182 attenuated AML development and extended the OS in the murine AML model. Most importantly, miR-182 was likely dispensable for normal hematopoiesis. Mechanistically, we identified BCL2 and HOXA9 as two key targets of miR-182 in this context. Most importantly, AML patients with miR-182 unmethylation had high expression of miR-182 followed by low protein expression of BCL2 and resistance to BCL2 inhibitor venetoclax (Ven) in vitro. Conclusions: Our results suggest that miR-182 is a potential therapeutic target for AML patients through attenuating the self-renewal of LSC but not HSPC. miR-182 promoter methylation could determine the sensitivity of Ven treatment and provide a potential biomarker for it.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , MicroRNAs , Animals , Mice , Cell Line, Tumor , DNA , Gene Expression Regulation, Leukemic , Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , MicroRNAs/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolismABSTRACT
Background: The incidence of Pneumocystis jirovecii pneumonia (PCP) has been increasing in patients with hematologic malignancies due to the use of glucocorticoid therapy and immunosuppressive medication. The reports of PCP in non-Hodgkin's lymphoma (NHL) after rituximab-based chemotherapy are still rare. We reported a case series of PCP in NHL to show the clinical features and prognosis in those patients. Methods: We conducted a retrospective review of 15 NHL patients who developed PCP after rituximab-based chemotherapy during June 30, 2014 to June 1, 2020. We analyzed the laboratory and radiographic findings for those patients through descriptive statistics analysis. Results: The study revealed that PCP in NHL patients was complicated by chemotherapy after about 4 courses (range, 2 to 6 courses). Most patients had a standard lymphocyte count before treatment, and 14 of 15 patients (93.3%) had lymphopenia at the time of diagnosis of PCP. In addition to typical symptoms such as fever and dyspnea at the diagnosis of PCP, most patients had abnormal laboratory indexes such as marked elevations of C-reactive protein (CRP) and lactic dehydrogenase (LDH) both before and at the time of diagnosis. The (1,3)-ß-D-glucan test was also revealed as a sensitive index for PCP. Bilateral ground-glass opacity was detected in 14 cases through computed tomography (CT) scans. Positive results of microbiological testing were observed in 7 cases; sputum culture was positive in 3 and next-generation sequencing (NGS) was positive in 3 of these 7 patients, and the other case was positive in both sputum culture and NGS. Patients received high-dose trimethoprim/sulfamethoxazole (TMP/SMZ), caspofungin, and steroids as the treatment for PCP. Ventilatory support was required by 3 patients, so they were admitted to the intensive care unit (ICU), and 1 patient died from PCP. Conclusions: Dynamic monitoring of CRP, LDH, and (1,3)-ß-D-glucan test during the treatment of NHL may have a predictive value for the diagnosis of PCP. Additionally, we should use NGS as a rapid and sensitive method for the early diagnosis of PCP. When patients are classified as 'probable PCP', early and effective treatment has obvious significance to improve the prognosis.
ABSTRACT
Venetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival.
ABSTRACT
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-PTMC169 block copolymer, forming mPEG-b-PTMC169@ABT-199 nanoparticles (abbreviated as PEG-ABT-199), which presented better aqueous dispersion and higher efficiency of loading and encapsulation than pure ABT-199. We then compared the anti-leukemic ability of pure ABT-199 and PEG-ABT-199 in vitro and in vivo. PEG-ABT-199 had a lower IC50 value compared with pure ABT-199 in MV4-11 and MOLM-13 cell lines. In addition, PEG-ABT-199 significantly induced apoptosis and decreased colony number than pure ABT-199. Most importantly, PEG-ABT-199 markedly reduced leukemic burden, inhibited the infiltration of leukemic blasts in the spleen, and extended the overall survival (OS) in MLL-AF9-transduced murine AML compared with free ABT-199. Meanwhile, the blank PEG169 NP was non-toxic to normal hematopoiesis in vitro and in vivo, suggesting that PEG169 NP is a safe carrier. Mechanistically, PEG-ABT-199 enhanced mitochondria-targeted delivery of ABT-199 to trigger the collapse of mitochondrial membrane potential (MMP), the release of cytochrome c (cyt-c), and mitochondria-based apoptosis. In conclusion, our results suggest that PEG-ABT-199 has more vital anti-leukemic ability than pure ABT-199. PEG-ABT-199 has potential application in clinical trials to alleviate side effects and improve anti-leukemia ability. STATEMENT OF SIGNIFICANCE: ATB-199, an orally selective inhibitor for BCL2 protein, presents marked activity in relapsed or refractory AML, T-ALL, and CLL patients. However, ABT-199 resistance severely limits the further clinical usage because of off-target effects, non-specific toxicities, and low delivery of drugs. To reduce the side-effects and improve the solubility and bioavailability, ABT-199 was encapsulated into the amphiphilic mPEG-b-PTMC block copolymer by co-assembly method to obtain mPEG-b-PTMC@ABT-199 nanoparticles (PEG-ABT-199). PEG-ABT-199 has several advantages compared with pure ABT-199. 1.PEG-ABT-199 presents better aqueous dispersion and higher efficiencies of loading and encapsulation than pure ABT-199. 2. PEG-ABT-199 substantially enhances the anti-leukemic ability in vitro and in vivo compared with pure ABT-199. 3. PEG-ABT-199 has little effects on normal cells. 4. PEG-ABT-199 can reduce treatment cost.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Nanoparticles , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Bridged Bicyclo Compounds, Heterocyclic , Cell Line, Tumor , Drug Delivery Systems , Drug Liberation , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Lipase/metabolism , Mice , Mitochondrial Membranes/metabolism , Polymers/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , SulfonamidesABSTRACT
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.
Subject(s)
Lymphoma, Mantle-Cell , Adenine/analogs & derivatives , Adult , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Humans , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/genetics , Phosphatidylinositol 3-Kinases/genetics , Piperidines , Proto-Oncogene Proteins c-bcl-2/genetics , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Tumor MicroenvironmentABSTRACT
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.
ABSTRACT
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.
Subject(s)
Bone Marrow/pathology , Curcumin/pharmacology , Hematopoiesis , Iron Overload/metabolism , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Sirtuin 3/metabolism , Superoxide Dismutase/metabolism , Acetylation/drug effects , Animals , Autophagy/drug effects , Bone Marrow/drug effects , Bone Marrow/metabolism , Cytoprotection/drug effects , Hematopoiesis/drug effects , Humans , Iron Overload/pathology , MiceABSTRACT
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.
Subject(s)
Apoptosis Regulatory Proteins , Leukemia, Myeloid, Acute , Neoplastic Stem Cells , Animals , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Up-Regulation , WT1 Proteins/geneticsABSTRACT
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 de novo non-M3 AML were enrolled in this study. Variables including gender, age, serum albumin, white blood cell (WBC) count, hemoglobin (Hb), platelet (PLT) count, blasts at peripheral blood (PB) and bone marrow (BM), immunophenotype and cytogenetics at diagnosis, BM response after one course of chemotherapy and hematopoietic stem cell transplantation (HSCT) treatment were studied. We found that normal albumin level (serum albumin >3.5 g/dL) was significantly associated with superior overall survival (HR = 0.375, p < .001) and leukemia-free survival (HR = 0.411, p < .001). These results demonstrate that albumin could serve as a simple, cheap, and objective prognostication factor in refinement of AML regimens.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hypoalbuminemia , Leukemia, Myeloid, Acute , Leukemia, Promyelocytic, Acute , Humans , Hypoalbuminemia/diagnosis , Leukemia, Myeloid, Acute/diagnosis , PrognosisABSTRACT
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.
Subject(s)
E1A-Associated p300 Protein/metabolism , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Sp1 Transcription Factor/metabolism , Transcription, Genetic , ras GTPase-Activating Proteins/genetics , Bone Marrow/metabolism , Bone Marrow/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Down-Regulation/genetics , E1A-Associated p300 Protein/genetics , Gene Expression Regulation, Neoplastic , Humans , Promoter Regions, Genetic , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/metabolism , Sp1 Transcription Factor/genetics , ras GTPase-Activating Proteins/metabolismABSTRACT
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 ß-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-ß-catenin axis. In conclusion, MLT might be a potential treatment for t (8;21) leukaemia by targeting AML1-ETO oncoprotein.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Leukemia/drug therapy , Melatonin/pharmacology , MicroRNAs/genetics , RUNX1 Translocation Partner 1 Protein/genetics , Animals , Apoptosis/drug effects , Binding Sites/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Self Renewal/drug effects , Chromosomes, Human, Pair 21/genetics , Chromosomes, Human, Pair 8/genetics , Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors , Disease Models, Animal , Humans , Leukemia/genetics , Leukemia/pathology , Mice , MicroRNAs/antagonists & inhibitors , Oncogene Proteins, Fusion/genetics , RUNX1 Translocation Partner 1 Protein/antagonists & inhibitors , Translocation, Genetic/drug effects , beta Catenin/geneticsABSTRACT
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.
Subject(s)
Gene Rearrangement , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-myc/genetics , Humans , Lymphoma, Large B-Cell, Diffuse/therapy , Molecular Targeted Therapy , PrognosisABSTRACT
The natural history of mantle cell lymphoma (MCL) is a continuous process with the vicious cycle of remission and recurrence. Because MCL cells are most vulnerable before their exposure to therapeutic agents, front-line therapy could eliminate MCL cells at the first strike, reduce the chance for secondary resistance, and cause long-term remissions. If optimized, it could become an alternative to cure MCL. The key is the intensity of front-line therapy. Both the Nordic 2 and the MD Anderson Cancer Center HCVAD trials, with follow-up times greater than 10 years, achieved long-term survivals exceeding 10 years. But the Achilles heel in both trials were the severe toxicities, such as secondary malignancies including myelodysplastic syndromes /leukemia. Therefore, intensive therapies can act as a double-edged sword providing long term survival at the cost of severe toxicities. In our opinion, although intensive chemotherapy can cause detrimental side effects, it is indispensable given that we run the risk of sacrificing long-term survivals in these young and fit patients. We must seek for a powerful alternative at the front-line. Furthermore, minimal residual disease negativity should be the optimal therapeutic goal to achieve before and after autologous stem cell transplantation. Some novel therapeutic strategies have shown to improve outcomes, but it is not yet clear as to how these results translate in population. Of note, MCL patients need to be stratified at diagnosis and be provided with different intensities of front-line regimen. In this review, we discuss current strategies for the treatment of young patients with newly diagnosed MCL.
Subject(s)
Lymphoma, Mantle-Cell/therapy , Adult , Aged , Female , Humans , Lymphoma, Mantle-Cell/pathology , Male , Middle AgedABSTRACT
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.
Subject(s)
Lymphoma, Mantle-Cell/drug therapy , Aged , Aged, 80 and over , Female , Humans , Lymphoma, Mantle-Cell/pathology , Male , Middle AgedABSTRACT
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.
Subject(s)
Lymphoma, Mantle-Cell/pathology , Neoplasm Regression, Spontaneous , Adult , Aged , Female , Fluorodeoxyglucose F18/metabolism , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Lymphoma, Mantle-Cell/diagnostic imaging , Lymphoma, Mantle-Cell/metabolism , Male , Middle Aged , Positron Emission Tomography Computed Tomography/methodsABSTRACT
To investigate the prognostic value of the red blood cell distribution width(RDW) recovery from low levels at diagnosis after completion of first line therapy in mutiple myeloma (MM)patients,we enrolled 78 consecutive patients with MM and followed up from 2005 to 2016 in our hospital. The RDW was measured following completion of first-line therapy.The log-rank test, univariate analysis, and Cox regression analysis were used to evaluate the relationship between RDW and survival. We found that patients with an RDW ≥ 15.5% at diagnosis, as well as at completion of first-line therapy, had significantly lower progression-free survival (PFS) and overall survival(OS) rates than those with an RDW < 15.5%(P < 0.05).Patients with RDW that maintained more than 15.5% upon completion of therapy showed a shorter OS (P < 0.05) and PFS (P < 0.05) compared with patients with an RDW that decreased to a lower level.The multivariate analysis showed that RDW ≥ 15.5% after the completion of first-line therapy were an independent prognostic marker of poorer OS (P = 0.044) and PFS (P = 0.034). Therefore,we demonstrated that RDW at diagnosis, as well as at completion of first-line therapy is an independent predictor for mutiple myeloma patients.RDW maintained at high level, irrespective of whether RDW decreased to the cutoff value predicted an unfavorable prognosis in patients with MM.