Erratum: CD31 promotes diffuse large B-cell lymphoma metastasis by upregulating OPN through the AKT pathway and inhibiting CD8+ T cells through the mTOR pathway.

[This corrects the article on p. 2656 in vol. 15, PMID: 37193155.].

Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS).

Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention.

Artesunate synergistically promotes sorafenib­induced apoptosis and ferroptosis in non­Hodgkin lymphoma cells through inhibition of the STAT3 pathway.

Despite the development of advanced therapies, the prognosis of non­Hodgkin lymphoma (NHL) remains unsatisfactory due to refractory and relapsed cases. Artesunate (ART) and sorafenib (SOR) both exert potential antitumor activity in lymphoma. The present study aimed to investigate whether ART and SOR produce synergistic anti­lymphoma effects, and to determine the potential underlying mechanisms. Cell viability assay, flow cytometry, malondialdehyde assay, GSH assay and western blotting were performed to evaluate cell viability, and changes in apoptosis, autophagic vacuoles, reactive oxygen species, mitochondrial membrane potential, lipid peroxidation and protein expression. The results demonstrated that ART and SOR synergistically inhibited the viability of NHL cells. ART and SOR also synergistically induced apoptosis, and markedly increased the expression levels of cleaved caspase­3 and poly (ADP­ribose) polymerase. Mechanistically, ART and SOR synergistically induced autophagy, and rapamycin enhanced the ART­ or SOR­induced inhibition of cell viability. Furthermore, it was demonstrated that ferroptosis promoted ART­ and SOR­induced cell death through increasing lipid peroxides. Erastin enhanced the inhibitory effects of ART and SOR on cell viability, whereas ferrostatin­1 reduced the ART­ and SOR­induced apoptosis of SU­DHL4 cells. Further studies revealed that signal transducer and activator of transcription 3 (STAT3) contributed to ferroptosis induced by ART and SOR in NHL cells, and genetic inhibition of STAT3 promoted ART/SOR­induced ferroptosis and apoptosis, concomitantly reducing the expression levels of glutathione peroxidase 4 and myeloid cell leukemia­1. Moreover, the combined treatment of ART and SOR exerted inhibitory effects on tumor growth, as well as antiangiogenic activity, resulting in the inhibition of CD31 expression in a xenograft model. Collectively, these findings indicated that ART acted synergistically with SOR to inhibit cell viability, and to induce apoptosis and ferroptosis through regulating the STAT3 pathway in NHL. Notably, ART and SOR may act as potential therapeutic agents for the treatment of lymphoma.

CD31 promotes diffuse large B-cell lymphoma metastasis by upregulating OPN through the AKT pathway and inhibiting CD8+ T cells through the mTOR pathway.

OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin's lymphoma. Invasive DLBCL cells are likely to metastasize into extranodal tissue (e.g., the central nervous system) that is difficult for chemotherapy drugs to penetrate, seriously affecting patient prognosis. The mechanism of DLBCL invasion remains unclear. This study investigated the association between invasiveness and platelet endothelial cell adhesion molecule-1 (CD31) in DLBCL. METHODS: This study consisted of 40 newly diagnosed DLBCL patients. Differentially expressed genes and pathways in invasive DLBCL cells were identified using real-time polymerase chain reaction, western blotting, immunofluorescence, and immunohistochemical staining, RNA sequencing, and animal experiments. The effect of CD31-overexpressing DLBCL cells on the interactions between endothelial cells was determined using scanning electron microscopy. The interactions between CD8+ T cells and DLBCL cells were examined using xenograft models and single-cell RNA sequencing. RESULTS: CD31 was upregulated in patients with multiple metastatic tumor foci compared to patients with a single tumor focus. CD31-overexpressing DLBCL cells formed more metastatic foci in mice and shortened mouse survival time. CD31 disrupted the tight junctions between endothelial cells of the blood-brain barrier by activating the osteopontin-epidermal growth factor receptor-tight junction protein 1/tight junction protein-2 axis through the protein kinase B (AKT) pathway, enabling DLBCL to enter the central nervous system to form central nervous system lymphoma. Furthermore, CD31-overexpressing DLBCL cells recruited CD31+ CD8+ T cells that failed to synthesize interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), and perforin via the activated mTOR pathway. Some target genes, such as those encoding S100 calcium-binding protein A4, macrophage-activating factor, and class I b-tubulin, may be used to treat this type of DLBCL surrounded by functionally suppressed CD31+ memory T cells. CONCLUSIONS: Our study suggests that DLBCL invasion is associated with CD31. The presence of CD31 in DLBCL lesions could represent a valuable target for treating central nervous system lymphoma and restoring CD8+ T-cell function.

CPEB2 enhances cell growth and angiogenesis by upregulating ARPC5 mRNA stability in multiple myeloma.

BACKGROUND: The process of multiple myeloma (MM) is the result of the combined action of multiple genes. This study aims to explore the role and mechanism of cytoplasmic polyadenylation element binding protein2 (CPEB2) in MM progression. METHODS: The mRNA and protein expression levels of CPEB2 and actin-related protein 2/3 complex subunit 5 (ARPC5) were assessed by quantitative real-time PCR and western blot analysis. Cell function was determined by cell counting kit 8 assay, soft-agar colony formation assay, flow cytometry and tube formation assay. Fluorescent in situ hybridization assay was used to analyze the co-localization of CPEB2 and ARPC5 in MM cells. Actinomycin D treatment and cycloheximide chase assay were performed to assess the stability of ARPC5. The interaction between CPEB2 and ARPC5 was confirmed by RNA immunoprecipitation assay. RESULTS: CPEB2 and ARPC5 mRNA and protein expression levels were upregulated in CD138+ plasma cells from MM patients and cells. CPEB2 downregulation reduced MM cell proliferation, angiogenesis, and increased apoptosis, while its overexpression had an opposite effect. CPEB2 and ARPC5 were co-localized at cell cytoplasm and could positively regulate ARPC5 expression by mediating its mRNA stability. ARPC5 overexpression reversed the suppressive effect of CPEB2 knockdown on MM progression, and it knockdown also abolished CPEB2-promoted MM progression. Besides, CPEB2 silencing also reduced MM tumor growth by decreasing ARPC5 expression. CONCLUSION: Our results indicated that CPEB2 increased ARPC5 expression through promoting its mRNA stability, thereby accelerating MM malignant process.

Mitochondrial dysfunction and drug targets in multiple myeloma.

Multiple myeloma (MM) is the second most common hematological cancer that has no cure. Although currently there are several novel drugs, most MM patients experience drug resistance and disease relapse. The results of previous studies suggest that aberrant mitochondrial function may contribute to tumor progression and drug resistance. Mitochondrial DNA mutations and metabolic reprogramming have been reported in MM patients. Several preclinical and clinical studies have shown encouraging results of mitochondria-targeting therapy in MM patients. In this review, we have summarized our current understanding of mitochondrial biology in MM. More importantly, we have reviewed mitochondrial targeting strategies in MM treatment.

A novel cuproptosis-related LncRNA signature: Prognostic and therapeutic value for acute myeloid leukemia.

Background: Cuproptosis is a type of programmed cell death that is involved in multiple physiological and pathological processes, including cancer. We constructed a prognostic cuproptosis-related long non-coding RNA (lncRNA) signature for acute myeloid leukemia (AML). Methods: RNA-seq and clinical data for AML patients were acquired from The Cancer Genome Atlas (TCGA) database. The cuproptosis-related prognostic lncRNAs were identified by co-expression and univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) was performed to construct a cuproptosis-related lncRNA signature, after which the AML patients were classified into two risk groups based on the risk model. Kaplan-Meier, ROC, univariate and multivariate Cox regression, nomogram, and calibration curves analyses were used to evaluate the prognostic value of the model. Then, expression levels of the lncRNAs in the signature were investigated in AML samples by quantitative polymerase chain reaction (qPCR). KEGG functional analysis, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. The sensitivities for potential therapeutic drugs for AML were also investigated. Results: Five hundred and three lncRNAs related to 19 CRGs in AML samples from the TCGA database were obtained, and 21 differentially expressed lncRNAs were identified based on the 2-year overall survival (OS) outcomes of AML patients. A 4-cuproptosis-related lncRNA signature for survival was constructed by LASSO Cox regression. High-risk AML patients exhibited worse outcomes. Univariate and multivariate Cox regression analyses demonstrated the independent prognostic value of the model. ROC, nomogram, and calibration curves analyses revealed the predictive power of the signature. KEGG pathway and ssGSEA analyses showed that the high-risk group had higher immune activities. Lastly, AML patients from different risk groups showed differential responses to various agents. Conclusion: A cuproptosis-related lncRNA signature was established to predict the prognosis and inform on potential therapeutic strategies for AML patients.

Microtransplantation for myeloid sarcoma: Two case reports.

Myeloid sarcoma (MS), is a rare extramedullary tumor with a poor prognosis and high recurrence rate. Microtransplantation is one of the alternative methods of traditional transplantation, which does not rely on HLA complete matching, has low toxicity and may retain part of graft-versus-leukemia (GVL) effect. It has been reported that microtransplantation can significantly improve the survival rate of elderly AML patients. At present, there is no report on the application of micro transplantation in MS. We will report two cases of MS treated by micro transplantation. The disease-free survival was 66 months and 55 months respectively.

Treatment of refractory MALT lymphoma by lenalidomide plus bendamustine: A case report.

RATIONALE: Marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) has an indolent natural course and disseminates slowly. However, there is currently no consensus regarding the optimal treatment strategy for relapsed/refractory MALT lymphomas. Lenalidomide-bendamustine may be an effective regimen for such cases. PATIENT CONCERNS: A 48-year-old Chinese male patient with MALT lymphoma and API2/MALT received 2 courses of standard-dose rituximab, cyclophosphamide, vincristine, prednisone regimen chemotherapy combined with Helicobacter pylori eradication therapy. However, this disease was not effectively managed. DIAGNOSIS: MALT lymphoma. INTERVENTIONS: The patient received lenalidomide-bendamustine (lenalidomide 25 mg on days 1-21 and bendamustine 90 mg/m2 on days 1-2) for 6 courses. OUTCOMES: Lenalidomide-bendamustine was a safe and effective chemotherapy. No serious adverse events occurred during the treatment period. Ultrasound gastroscopy revealed that the tumor gradually shrank and eventually disappeared to complete remission. LESSONS: The lenalidomide-bendamustine scheme might be a potentially effective option for patients with refractory or relapsed MALT lymphoma.

RIPK1 inhibition enhances the therapeutic efficacy of chidamide in FLT3-ITD positive AML, both in vitro and in vivo.

Acute myeloid leukemia (AML) with FLT3-ITD mutation accounts for a large proportion of relapsed/refractory AML with poor prognosis. RIPK1 is a known key regulator of necroptosis and RIPK1 inhibition shows anti-AML effects in vitro. Chidamide is a histone deacetylase inhibitor (HDACi) with proven ability to induce apoptosis in FLT3-ITD positive AML cells. In the present study, we evaluated the effects of the combination of 22b, a novel RIPK1 inhibitor, and chidamide on proliferation and apoptosis in FLT3-ITD positive AML cell lines and primary cells. The results showed that 22b could significantly enhance the anti-leukemia effect of low-dose chidamide both on cell lines and primary cells. In a subcutaneous xenograft AML model, the combination of 22b and chidamide exhibited obviously elevated anti-tumor activity. In conclusion, our results support that the combination of RIPK1 inhibitor 22b and chidamide may be a novel therapeutic avenue for FLT3-ITD positive AML patients.

Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling.

Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.

Causes of death and effect of non-cancer-specific death on rates of overall survival in adult classic Hodgkin lymphoma: a populated-based competing risk analysis.

BACKGROUND: The improved prognosis of classic Hodgkin lymphoma (cHL) has been accompanied by elevated risks of non-cancer-specific death (non-CSD). The aim of this study was to verify the occurrence of non-CSD and its effect on rates of overall survival among adult patients with cHL. METHODS: To ensure sufficient follow-up time, we analyzed retrospective data from patients aged ≥20 years with cHL that was diagnosed between 1983 and 2005 in the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was applied to analyze the non-CSD occurrence in relation to all factors. Using Fine-Gray's method, we calculated the cumulative incidences of CSD and non-CSD. Stacked cumulative incidence plots and ratio of non-CSD to all causes of death were applied to evaluate the effect of non-CSD on rates of overall survival. Finally, we analyzed long-term mortality through Cox proportional hazard regression analysis and competing risk regression analysis to emphasize a more appropriate model of survival for patients with cHL. RESULTS: Among the 18,518 patients included, there were 3768 cases of CSD (20.3%) and 3217 of non-CSD (17.4%). Older age, earlier period, male sex, unmarried status, mixed cellularity (MC) and lymphocyte-depletion (LD) histological subtype, and patients received radiotherapy (RT) only were associated with more non-CSD according to binary logistic analysis. The cumulative incidence of non-CSD exceeded CSD after approximately 280 months follow-up. The most common causes of non-CSDs were cardiovascular disease, subsequent primary neoplasms, infectious diseases, accidents, and suicide. In a Cox proportional hazards model, patients who were black, unmarried, at an advanced stage or underwent chemotherapy (CT) alone were at greater risk of mortality than were white patients, who were married, at an early stage, and underwent combined modality; these populations were also found to be at greater risk for CSD in a competing risk model, but the risk of non-CSD did not differ significantly according to race and marital status, patients with early-stage disease and who underwent RT only were found to be at higher risk of non-CSD instead. CONCLUSIONS: Lymphoma was the cause of death in most patients who died, but non-CSD was not unusual. Patients with cHL should be monitored closely for signs of cardiovascular disease and malignant tumors. Rates of overall survival of patients were diminished by non-CSD, and a competing risk model was more suitable for establishing the prognosis than was the Cox proportional hazards model.

[Efficacy of Different Doses of Daunorubicin Induced Chemotherapy in Patients with Newly Diagnosed Primary Acute Myeloid Leukemia Under 65 Years Old].

OBJECTIVE: To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. METHODS: The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ï¼»75 mg/(m2·d)ï¼½ and 51 cases in the standard-dose group ï¼»60 mg/(m2·d)ï¼½. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. RESULTS: Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3－4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITD－ AML patients. CONCLUSION: The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.

Treatment of refractory diffuse large B-cell lymphoma by chidamide combined with autologous stem cell transplantation: a case report.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with certain DLBCLs affecting specific anatomic sites, such as primary cutaneous DLBCL, leg type and intravascular large B-cell lymphoma. However, the occurrence of secondary cutaneous involvement in DLBCL while patients are undergoing regular chemotherapy is rare. In this study, we reported a case of refractory diffuse large B-cell lymphoma with cutaneous involvement that achieved complete remission for more than 4 years with epigenetic regulation of chidamide in combination with chemotherapy and autologous hematopoietic stem cell transplantation including a pretreatment regimen containing chidamide.

Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway.

Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3ß, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.

The derived neutrophil-lymphocyte ratio and the neutrophil-lymphocyte ratio are related to poor prognosis in Hodgkin lymphoma patients.

INTRODUCTION: The inflammatory and immune cells have an important impact on Hodgkin lymphoma (HL). The derived neutrophil-lymphocyte ratio (dNLR) has been confirmed to have a similar prognostic value as the neutrophil-lymphocyte ratio (NLR) in many kinds of tumors, but it has not been explored as a prognostic marker for Hodgkin lymphoma patients. OBJECTIVE: The aim of the study is to evaluate the prognostic value of dNLR and NLR in HL. METHODS: This retrospective study included 213 newly diagnosed HL patients from 2008 to 2019. Then, the prognostic significance of dNLR and NLR in these patients was evaluated. Meanwhile, subgroup analyses based on the Ann Arbor stage and histotype were also carried out. Finally, propensity score matching was used to reduce selection bias. RESULTS: Patients with dNLR ≥ 2.1 showed shorter overall survival (OS) (P = 0.006). Also, patients with NLR ≥ 3.0 showed worse OS (P = 0.005) and progression-free survival (PFS) (P = 0.031). These results were also found in patients with early-stage and mixed cellularity subtype HL. Besides, high dNLR represented an independent prognostic marker for OS and high NLR remained an independent prognostic factor for OS and PFS on multivariable analysis. CONCLUSION: Elevated dNLR and NLR were related to worse survival in HL patients. For the first time, the dNLR has shown the potential to be a new prognostic factor for patients with HL.

Aberrant LncRNA Expression in Leukemia.

Leukemia is a common malignant cancer of the hematopoietic system, whose pathogenesis has not been fully elucidated. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides without protein-coding function. Recent studies report their role in cellular processes such as the regulation of gene expression, as well as in the carcinogenesis, occurrence, development, and prognosis of various tumors. Evidence indicating relationships between a variety of lncRNAs and leukemia pathophysiology has increased dramatically in the previous decade, with specific lncRNAs expected to serve as diagnostic biomarkers, novel therapeutic targets, and predictors of clinical outcomes. Furthermore, these lncRNAs might offer insight into disease pathogenesis and novel treatment options. This review summarizes progress in studies on the role(s) of lncRNAs in leukemia.

Aberrant TRPM4 expression in MLL-rearranged acute myeloid leukemia and its blockade induces cell cycle arrest via AKT/GLI1/Cyclin D1 pathway.

Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p = .028), M4/M5 subtype (p = .000), FLT3-ITD mutation (p = .034), MLL status (p = .007) and a higher risk stratification (p = .001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL-rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL-rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL-rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression.