The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding both AML genetics and epigenetics. MicroRNAs (miRNAs) play important roles in cell proliferation, differentiation, and survival and may be useful for AML diagnosis and prognosis. In this study, a novel miRNA, hsa-miR-12462, was identified in bone marrow (BM) samples from AML patients at diagnosis by small RNA sequencing. A significant higher level of hsa-miR-12462 was found in patients who achieve complete remission (AML-CR) after induction therapy compared with those who suffer relapse/refractory (AML-RR). FosB was predicted to be the target of hsa-miR-12462 through RNA sequencing, bioinformatics analysis, and protein-protein interaction (PPI) network analysis and then verified by luciferase activity assay. T-5224, the inhibitor of FosB, was administered to AML cell lines, which could inhibit cell proliferation, promote apoptosis, and restore the sensitivity of AML cells to cytarabine (Ara-C). In summary, a higher level of hsa-miR-12462 in AML cells is associated with increased sensitivity to Ara-C via targeting FosB.
Acute myeloid leukemia (AML) is a threatening hematological malignant disease in which new successful approaches in therapy are needed. Cyclin-dependent kinase 6 ( CDK6 ), a regulatory enzyme of the cell cycle that plays an important role in leukemogenesis and the maintenance of leukemia stem cells (LSC), has the potential to predict the prognosis of AML. By analyzing public databases, we observed that the messenger RNA (mRNA) levels of CDK6 were significantly overexpressed in AML cell lines and non-acute promyelocytic leukemia (non-APL) AML patients when compared to healthy donors. Furthermore, CDK6 expression was significantly reduced in AML patients who achieved complete remission (CR) compared to that at the time of diagnosis in our validated cohort. The expression of CDK6 was tightly correlated with peripheral blood blasts, French–American–British (FAB) subtypes, CCAAT-enhancer-binding protein α (CEBPA) mutation, and chromosomal abnormalities of t(8;21). However, the clinical significance and effects of CDK6 expression on the prognosis of non-APL AML patients remain uncertain. We found that CDK6 expression was inversely correlated with overall survival (OS) among non-APL AML patients using the Kaplan–Meier analysis. CDK6 was also found to be positively associated with genes identified to contribute to the development of leukemia, including CCND2 , DNMT3B , SOX4 , and IKZF2 , as well as being negatively associated with anticancer microRNAs, including miR-187, miR-9, miR-582, miR708, and miR-362. In summary, our study revealed that CDK6 might be a potential diagnostic and prognostic biomarker in non-APL AML patients.
ABSTRACT T‐cell acute lymphoblastic leukaemia (T‐ALL) is a heterogeneous malignant disease with high relapse and mortality rates. To characterise the multiomics features of T‐ALL, we conducted integrative analyses using single‐cell RNA, TCR and chromatin accessibility sequencing on pre‐ and post‐treatment peripheral blood and bone marrow samples of the same patients. We found that there is transcriptional rewiring of gene regulatory networks in T‐ALL cells. Some transcription factors, such as TCF3 and KLF3 , showed differences in activity and expression levels between T‐ALL and normal T cells and were associated with the prognosis of T‐ALL patients. Furthermore, we identified multiple malignant TCR clonotypes among the T‐ALL cells, where the clonotypes consisted of distinct combinations of the same TCR α and β chain per patient. The T‐ALL cells displayed clonotype‐specific immature thymocyte cellular characteristics and response to chemotherapy. Remarkably, T‐ALL cells with an orphan TCRβ chain displayed the strongest stemness and resistance to chemotherapy. Our study provided transcriptome and epigenome characterisation of T‐ALL cells categorised by TCR clonotypes, which may be helpful for the development of novel predictive markers to evaluate treatment effectiveness for T‐ALL.
The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.
Abstract Background The identification of survival predictors is crucial for early intervention to improve outcome in acute myeloid leukemia (AML). This study aim to identify chest computed tomography (CT)-derived features to predict prognosis for acute myeloid leukemia (AML). Methods 952 patients with pathologically-confirmed AML were retrospectively enrolled between 2010 and 2020. CT-derived features (including body composition and subcutaneous fat features), were obtained from the initial chest CT images and were used to build models to predict the prognosis. A CT-derived MSF nomogram was constructed using multivariate Cox regression incorporating CT-based features. The performance of the prediction models was assessed with discrimination, calibration, decision curves and improvements. Results Three CT-derived features, including myosarcopenia, spleen_CTV, and SF_CTV (MSF) were identified as the independent predictors for prognosis in AML ( P < 0.01). A CT-MSF nomogram showed a performance with AUCs of 0.717, 0.794, 0.796 and 0.792 for predicting the 1-, 2-, 3-, and 5-year overall survival (OS) probabilities in the validation cohort, which were significantly higher than the ELN risk model. Moreover, a new MSN stratification system (MSF nomogram plus ELN risk model) could stratify patients into new high, intermediate and low risk group. Patients with high MSN risk may benefit from intensive treatment ( P = 0.0011). Conclusions In summary, the chest CT-MSF nomogram, integrating myosarcopenia, spleen_CTV, and SF_CTV features, could be used to predict prognosis of AML.
Abstract MicroRNAs (miRNAs) play important roles in cell proliferation, differentiation, and survival and may be useful for acute myeloid leukemia (AML) diagnosis and prognosis. In this study, we defined a novel miRNA, hsa-miR-12462, through small RNA sequencing of the bone marrow (BM) cells from 128 AML patients. Overexpression of hsa-miR-12462 in AML cells (U937 and HL-60) significantly decreased their growth rate when compared with those of the wild-type and MOCK controls. In a xenograft mouse model, tumor weight and size in the mice bearing the U937 cells with hsa-miR-12462 overexpression were significantly reduced when compared with those bearing the mock cells. The AML cells overexpressing hsa-miR-12462 had increased sensitivity to cytarabine chemotherapy. Combining the data from the MiRDB, an online microRNA database ( http://mirdb.org ), with the RNA-sequencing results, SLC9A1 was predicted to be one of the targets of hsa-miR-12462. hsa-miR-12462 was further confirmed to bind exclusively to the 3′UTR of SLC9A1 in U937 cells, leading to downregulation of SLC9A1. In summary, a higher level of hsa-miR-12462 in AML cells is associated with increased sensitivity to cytarabine chemotherapy via downregulation of SLC9A1.
Evading apoptosis by overexpression of anti-apoptotic Bcl-2 family proteins is a hallmark of cancer cells and the Bcl-2 selective inhibitor venetoclax is widely used in the treatment of hematologic malignancies. Mcl-1, another anti-apoptotic Bcl-2 family member, is recognized as the primary cause of resistance to venetoclax treatment. However, there is currently no Mcl-1 inhibitor approved for clinical use.Paired parental and Mcl-1 knockout H1299 cells were used to screen and identify a small molecule named MI-238. Immunoprecipitation (IP) and flow cytometry assay were performed to analyze the activation of pro-apoptotic protein Bak. Annexin V staining and western blot analysis of cleaved caspase 3 were employed to measure the cell apoptosis. Mouse xenograft AML model using luciferase-expressing Molm13 cells was employed to evaluate in vivo therapeutic efficacy. Bone marrow samples from newly diagnosed AML patients were collected to evaluate the therapeutic potency.Here, we show that MI-238, a novel and specific Mcl-1 inhibitor, can disrupt the association of Mcl-1 with BH3-only pro-apoptotic proteins, selectively leading to apoptosis in Mcl-1 proficient cells. Moreover, MI-238 treatment also potently induces apoptosis in acute myeloid leukemia (AML) cells. Notably, the combined treatment of MI-238 with venetoclax exhibited strong synergistic anti-cancer effects in AML cells in vitro, MOLM-13 xenografts mouse model and AML patient samples.This study identified a novel and selective Mcl-1 inhibitor MI-238 and demonstrated that the development of MI-238 provides a novel strategy to improve the outcome of venetoclax therapy in AML.
Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)