Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. METHODS: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. RESULTS: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. CONCLUSIONS: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.).

Patient-Reported Outcomes in Young Adults with Myeloproliferative Neoplasms.

INTRODUCTION: Genetic landscape, disease characteristics, and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. METHODS: We conducted a multicenter, cross-sectional study to compare the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (>60 years). RESULTS: Of the 1,664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV, and 71 (20.3%) with MF. In multivariate analyses, the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. CONCLUSIONS: We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.

Expression of PD-L1 on regulatory B cells in patients with acute myeloid leukaemia and its effect on prognosis.

Programmed death-ligand 1 (PD-L1) is involved in immunosuppression in variety of tumours. Regulatory B cells (Bregs) are critical immune regulatory cells, and it has been demonstrated that the number of regulatory B cells in patients with acute myeloid leukaemia (AML) is much higher than that in healthy donors (HDs), which is linked to a poor prognosis. This study aimed to determine whether increased expression of PD-L1, including in Bregs, is associated with a worse prognosis in individuals with AML. The proportion of Bregs, PD-L1 expression in Bregs and PD-1 expression in T cells were determined using flow cytometry using patient samples from 21 newly diagnosed AML patients at different stages of treatment and 25 HDs. We confirmed PD-L1 expression in Bregs, and PD-1 expression in CD3+ CD4+ T cells in bone marrow and peripheral blood samples from AML patients was higher than that in samples from HDs. The complete remission (CR) and progression-free survival (PFS) of Bregs with high PD-L1 expression were significantly decreased following induction chemotherapy. PD-L1 expression is indeed increased in Bregs from individuals with AML, and high PD-L1 expression is related to a poor prognosis.

Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): a phase II, single-arm study.

BACKGROUND: Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM. METHODS: The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses. RESULTS: A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients. CONCLUSIONS: With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

A concise prognostic score system for diffuse large B-cell lymphoma: a retrospective study with long-term follow-up.

Aim: To identify risk factors and establish a concise prognostic scoring system in patients with diffuse large B-cell lymphoma (DLBCL). Methods: A total of 131 DLBCL patients were enrolled with long-term follow-up who were treated in Shengjing Hospital of the China Medical University. The relationship between clinical parameters and outcomes was analyzed. Results: Multivariate analysis showed that patient age, BMI, CA125 and rituximab application were independent risk factors. Thereafter, a concise scoring system was established, and the new system could identify high-risk patients (p < 0.0001). The patients were divided into three groups: low-risk, medium-risk and high-risk groups. There were significant differences among different groups on overall survival and progression-free survival by log-rank test (p < 0.05). Conclusion: Old age, low BMI, high CA125 and no rituximab application were independent risk factors for DLBCL. The new established prognostic score system, which includes all the risk factors, could identify high-risk patients.

Lay abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma. Different clinical performance and treatment options lead to different outcomes. Identifying factors that indicate poor prognosis is helpful for clinicians to plan a suitable treatment regimen. Therefore, it is important to establish a concise prognostic scoring system to identify high-risk DLBCL patients. This retrospective study analyzed 131 DLBCL patients with long-term follow-up with R-CHOP or E-CHOP therapy regimen. The result showed that patients' age, BMI, CA125 and chemotherapy regimens with or without rituximab were independent risk factors. Thereafter, we established a concise scoring system, which scored each risk factor including old age, low BMI, high CA125 and no rituximab application as 1 point each. Definition of low-risk (0­1 point), medium-risk (2 points) and high-risk (3­4 points) groups indicated significant differences in prognosis.

Expression and Relationship of SAMHD1 with Other Apoptotic and Autophagic Genes in Acute Myeloid Leukemia Patients.

BACKGROUND: SAM domain- and HD domain-containing protein 1 (SAMHD1) is a cellular enzyme which is responsible for blocking replication in viruses and participates in the progression of many cancers. OBJECTIVE: The aim of this study was to correlate the expression level of SAMHD1 with other apoptotic and autophagic genes in acute myeloid leukemia (AML) patients. METHODS: In the present study, mRNA levels of SAMHD1 with other apoptotic and autophagic-related genes were evaluated in patients who were newly diagnosed with AML. RESULTS: SAMHD1, Bcl-xl, Bax, Bak, XIAP, and cIAP1 were downregulated in the AML group compared to the non-AML group (p < 0.05). SAMHD1 expression did not correlate with the other genes, while most apoptotic genes were positively correlated with each other. SAMHD1 expression was not associated with the blood routine or blast percentage of the AML patients, while Bax, Bak, cIAP2, and LC3 were significantly correlated with white blood cells. No statistically significant differences were found between the studied genes and prognosis stratifications, but Bcl-xl, Bak, cIAP1, and Mcl-1, LC3 were expressed at lower levels in the unfavorable AML group compared to the controls. CONCLUSION: SAMHD1 and Bcl-xl, Bax, Bak, XIAP, and cIAP1 were downregulated in AML patients, while there were no significant differences in the clinical characteristics and prognosis with reference to SAMHD1 expression.

Peripheral Absolute Lymphocyte Count: An Economical and Clinical Available Immune-Related Prognostic Marker for Newly Diagnosed Multiple Myeloma.

BACKGROUND To find economical and clinically available immune-related prognostic markers that could predict the overall survival (OS) of newly diagnosed multiple myeloma (NDMM) in the new drug era. MATERIAL AND METHODS Absolute lymphocyte count (ALC) and absolute monocyte count (AMC) were measured in routine blood samples from 102 patients with NDMM, and the lymphocyte-monocyte ratio (LMR) was derived. All the patients were receiving bortezomib-based chemotherapy as induction treatment. Log-rank testing was used for comparing the differences between groups. Univariate and multivariate tests were used to identify prognostic markers. RESULTS The median ALC and LMR values at diagnosis were 1.43×109/L and 3.7, respectively, and served as the cutoff point. As prognostic factors, ALC, LMR, and a new staging system combining ALC and the ISS staging system (L-ISS) were expected to have a significant impact on predicting OS. Furthermore, multivariate analysis showed that ALC ≥1.43×109/L (hazard ratio [HR]: 0.223; 95% confidence interval [CI]: 0.071-0.705; P=0.011), LMR ≥3.7 (HR: 0.363; 95% CI: 0.139-0.947; P=0.038), and L-ISS late stage (HR: 1.619; 95% CI: 1.065-2.743; P=0.027) were independent predictors for OS. CONCLUSIONS ALC and LMR can serve as surrogate markers for patients' antitumor immunity at the initial diagnosis of multiple myeloma. A new immune-related staging system, L-ISS, which combines ALC and the ISS staging system, can predict clinical outcomes in patients who are receiving bortezomib-based chemotherapy.

The Role of Regulatory B Cells in Patients with Acute Myeloid Leukemia.

BACKGROUND Regulatory B (Breg) cells are a group of B cells with immunomodulatory function, which mainly exert negative immunomodulatory function by secreting IL-10 and other cytokines. Due to their immunoregulatory properties, Breg cells may participate in the pathogenesis of acute myeloid leukemia (AML). This study was designed to explore the frequency of Breg cells and the relationship between the Breg cells and clinical data in patients with AML. MATERIAL AND METHODS A total of 46 (36 in peripheral blood, 10 in bone marrow) AML patients and 15 healthy donors (HD) were included for detection of Breg cells frequency by multicolor flow cytometry. All cases were divided into different groups according to FAB subtypes of leukemia, white blood cell count (WBC) levels, age, cytogenetic characteristics, and molecular abnormalities, and were compared the differences of Breg cell frequency. Survival curve analysis was performed to estimate the value of Breg cell frequency in prognosis among cases with AML. RESULTS We found that the frequency of Breg cells was higher in AML patients both in peripheral blood (PB) and in bone marrow (BM) compared with those in HDs. The AML patients with high WBC levels had higher Breg cell frequency compared with those with low WBC levels. Low-risk patients with had lower Breg cells frequency compared to the medium-risk patients. The patients with high WBC and high Breg cells frequency showed a shorter overall survival. Similarly, the overall survival of AML patients in the older group with high Breg cells frequency was significantly shorter than in the younger group with low Breg cell frequency. CONCLUSIONS For AML patients, the frequency of Breg cells was elevated, and high frequency of Breg cells may reveal poor prognosis.

DACT1 overexpression inhibits proliferation, enhances apoptosis, and increases daunorubicin chemosensitivity in KG-1α cells.

DACT1 has been shown to participate in the development of many types of tumors; however, its role and precise molecular mechanisms in leukemia are unclear. In this study, we investigated the effect of DACT1 on KG-1α leukemia cells to further understand the mechanisms of DACT1-mediated tumor suppression. We transfected a DACT1 expression plasmid to upregulate DACT1 in KG-1α cells and analyzed the resulting phenotypic changes. The results demonstrated that DACT1 overexpression inhibited KG-1α proliferation, increased apoptosis, and arrested cells in the G0/G1 phase. Mechanistically, DACT1 overexpression inhibited Wnt/ß-catenin signaling by reducing nuclear ß-catenin levels in KG-1α cells. Furthermore, the viability of KG-1α cells transfected with DACT1 was significantly reduced when treated with daunorubicin. We also found that DACT1 reduced P-glycoprotein expression in KG-1α cells. These findings revealed an inhibitory role for DACT1 in leukemogenesis and provided evidence that DACT1 is an attractive target for the development of novel anti-leukemia therapies.

Hypomethylation agent decitabine restores drug sensitivity by depressing P-glycoprotein activity through MAPK signaling pathway.

The multidrug resistance (MDR) continues to be an obstacle in the treatment of both hematological and solid tumors. Hypomethylation agent, decitabine (5-Aza-dC), is an experimental agent in MDR therapy, while the mechanism is not very clear. In the present study, we demonstrated 5-Aza-dC may reverse MDR induced by P-glycoprotein (P-gp) coded by mdr1 gene in both hematologic K562/ADR cells and solid tumor MCF-7/ADR cells with time and dose-dependent manner. 5-Aza-dC significantly increased drug sensitivity in patients' leukemic cells which had higher expression of mdr1 gene. Both total protein and membrane P-gp expression were up-regulated with 5-Aza-dC treatment in K562/ADR and MCF-7/ADR cells. However, accumulation of adriamycin and rhodamine 123 were increased which suggested the depression of P-gp activity. Gene expression profiling was performed and activation of MAPK signaling pathway was identified as the most significant change affected by 5-Aza-dC. Inhibition of MAPK pathway could increase P-gp activity. Our data suggested that hypomethylation agent decitabine restores drug sensitivity in the P-gp-induced MDR phenotype by depressing of P-gp activity as drug pump partly through MAPK signaling pathway.

Live kinase B1 maintains CD34+CD38- AML cell proliferation and self-renewal.

Live kinase B1 (LKB1) has been recognized as a tumor suppressor in many human cancers; however, LKB1 maintains self-renewal of hematopoietic stem cells (HSCs). The existence of leukemia stem cells (LSCs) is responsible for drug resistance and leukemia relapse. In acute myeloid leukemia (AML), CD34+CD38- fraction is the most enriched compartment for LSCs. We found that LKB1 was upregulated in CD34+CD38- AML cells. LKB1 downregulation suppressed the long-term proliferation of CD34+CD38- AML cells, induced CD34+CD38- AML cells into G2/M phase, and enhanced the sensitivity of CD34+CD38- AML cells to chemotherapy. Furthermore, LKB1 downregulation in CD34+CD38- AML cells inhibited tumor formation in NOD-SCID mice. Downregulation of LKB1 gene makes LSCs partly loose the characters as stem cells. Gene expression microarray showed that MAPK/ERK pathway was implicated in the regulation of CD34+CD38- AML cell proliferation by LKB1. Together, these findings demonstrate that LKB1 plays an important role in the maintenance of LSCs, which may be responsible for drug resistance and AML relapse.

Epidemiology and treatment of invasive fungal diseases in patients with multiple myeloma: findings from a multicenter prospective study from China.

The aim of this study is to investigate the epidemiology, diagnosis, treatment and risk factors of multiple myeloma patients with invasive fungi disease (IFD) in China. We analyzed multiple myeloma (MM) patients receiving chemotherapy in a prospective multicenter study. Basic characteristics, the diagnosis, and treatment of IFD were recorded. A total of 395 MM patients were enrolled, who received a total of 443 chemotherapy courses. Among them, 17 IFDs were diagnosed during one chemotherapy course. Fourteen of these were possible IFD and 3 were probable IFD. Ten of the 14 patients with possible IFD had lung infection. Thirty eight (8.6 %) patients received antifungal prophylaxis, and 47.4 % of them were administered with fluconazole. Patients who had a history of IFD or underwent a combined therapy with two antibiotics for over 7 days and with a history of granulocytopenia or ductus venosus insertion were more likely to be treated with antifungal prophylaxis. All of first-line antifungal therapies were monotherapy. Eleven (84.6 %) cases were treated with azoles. The median time of initial antifungal therapy was 8 days. The general condition of two patients with probable IFD and 10 patients (90.9 %) with possible IFD improved, while 1 patient with possible IFD died. Multivariate analysis revealed that history of IFD is an independent risk factor of IFD. The present multicenter study suggests that the incidence of IFD per chemotherapy courses in MM patients is 3.8 % and most patients are labelled as having possible IFD. Fluconazole is the most common antifungal agent for prophylaxis and voriconazole for therapeutic treatment. Previous IFD is a probable independent risk factor of IFD in MM patients receiving chemotherapy.

GDC-0152 induces apoptosis through down-regulation of IAPs in human leukemia cells and inhibition of PI3K/Akt signaling pathway.

The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling.

The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation.

The present study was designed to explore the effects of low-toxicity Embelin on TRAIL-induced apoptosis and its possible mechanism in human leukemia cells. Our study showed that low-toxicity Embelin enhanced TRAIL-induced apoptosis through DR4 and DR5 upregulation and caspase activation in HL-60 cells. Pan-caspase inhibitor Z-VAD-FMK inhibited cell apoptosis induced by TRAIL alone or combined with low-toxicity Embelin, which indicated the cytotoxic effect is mediated by caspase-dependent apoptosis. Although Embelin is an X chromosome-linked inhibitor-of-apoptosis protein (XIAP) inhibitor, an XIAP independent effect on cell death was detected in HL-60 cells exposed to low-toxicity Embelin and TRAIL. Low-toxicity Embelin upregulated DR4 and DR5 expression to enhance TRAIL-induced apoptosis. The sensitizing effects of Embelin on TRAIL-induced apoptosis were markedly attenuated when DR4/DR5 was knocked down. These data suggested that low-toxicity Embelin enhanced TRAIL-induced cell apoptosis through DR4 and DR5 upregulation, indicating that combination of low-toxicity Embelin and TRAIL may become as a potential antileukemia strategy.

Knockdown of RLIP76 expression by RNA interference inhibits proliferation, enhances apoptosis, and increases chemosensitivity to daunorubicin in U937 leukemia cells.

RLIP76 is known to play a role in cell growth, division, apoptosis, and chemosensitivity in various malignant cancer cells. However, few studies have been done on the role of RLIP76 in leukemia. In this study, human leukemia cell line U937 was transiently transfected with a RLIP76-targeted short hairpin RNA (shRNA) to investigate the effects of RLIP76 on cellular functions. Real-time PCR and western blot analysis revealed that the expression levels of RLIP76 mRNA and protein in U937 cells were significantly suppressed after transfection with shRNA-containing vector. Knockdown of RLIP76 significantly inhibited cell growth and decreased the colony formation rate, as assessed by trypan blue exclusion and colony formation assay. Flow cytometry analysis showed that reduced RLIP76 expression resulted in cell cycle arrest at G1 phase and induced apoptosis. Meanwhile, western blot analysis demonstrated that RLIP76 knockdown increased expression of Bax, cleaved caspase-3/-9, and cleaved poly (ADP-ribose) polymerase (PARP) but reduced the expression of cyclin D1, cyclin E, and Bcl-2 in U937 cells. Finally, knockdown of RLIP76 in U937 cells also enhanced their chemosensitivity to daunorubicin. Taken together, this study suggests that RLIP76 is a potential target for developing novel therapeutic strategies for leukemia.

Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia.

The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.

Long noncoding RNA LINC00675 drives malignancy in acute myeloid leukemia via the miR-6809 -CDK6 axis.

Hematological malignancies such as acute myeloid leukemia (AML) have a low cure rate and a high recurrence rate. Long noncoding RNAs (LNCs) are essential regulators of tumorigenesis and progression. The role of lncRNA LINC00675 in AML has rarely been reported. This study revealed elevated LINC00675 expression in AML that promotes proliferation and inhibits apoptosis. Mechanistically, LINC00675 combines with miR-6809 to promote the expression of CDK6 in vitro and in vivo. Immune-checkpoint genes were expressed more highly in LINC00675-high patients. A high level of LINC00675 expression may make patients more susceptible to palbociclib treatments. In conclusion, our study demonstrated that LINC00675 is an oncogenic lncRNA that enhances the malignancy of AML by upregulating CDK6 expression through miR-6809 sponging, providing a new perspective and feasible target for the diagnosis and treatment of AML.

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. RESULTS: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. CONCLUSION: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.