: Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.

Background: The ratio of C-reactive protein to albumin (CAR) is an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in several solid tumours and chronic lymphocytic leukaemia (CLL). However, no studies have investigated the prognostic value of the CAR in patients with acute myeloid leukaemia (AML). Objectives and Methods: We retrospectively analysed 212 newly diagnosed non-M3 AML patients. Using the receiver operating characteristic curve (ROC) method, the optimal cut-off value for CAR was determined. We investigated the correlations of the pretreatment CAR levels with clinical characteristics, treatment response of induction chemotherapy, overall survival (OS) and event-free survival (EFS). We also assessed the prognostic value of the CAR compared with other inflammation-based prognostic parameters by the area under the curve (AUC). Results: According to the ROC curve, the optimal cut-off value of CAR was 1.015. CAR was associated with age, C-reactive protein (CRP) levels, albumin levels, ferritin levels, bone marrow blast percentage, French-American-British (FAB) classification, immunophenotype and 2017 European Leukemia Net (2017 ELN) risk stratification. Importantly, we found that high CAR was a powerful indicator of a lower complete remission (CR) rate (p< 0.001), worse OS (p< 0.001) and worse EFS (p< 0.001). Subgroup analysis showed that a high CAR was associated with shorter OS and EFS in patients with intermediate risk stratification or those aged ≤ 65 years or those without haematopoietic stem cell transplantation (HSCT). In the multivariate analysis, the CAR was an independent prognostic factor for OS and EFS. Furthermore, the predictive value of CAR for OS is superior to that of CRP, albumin and GPS in de novo AML patients aged ≤ 65 years old. Conclusion: CAR is a simple and effective prognostic marker in patients with AML. It could be an additional prognostic factor that help further precise the current risk stratification of non-M3 AML, particularly for patients in intermediate risk stratification and those aged ≤ 65 years and those who did not undergo HSCT.

BACKGROUND: Mitosis-associated genes are dysregulated in many types of cancers and play important roles in disease progression and chemotherapy resistance. However, their expression and functions in chemotherapy-resistant Acute Myeloid Leukemia (AML) are still largely undetermined. OBJECTIVE: This study aims to explore the roles of spindle assembly checkpoint (SAC) genes CENPE, CENPF, and DLGAP5 in chemotherapy-resistant AML. METHODS: RNA-sequencing (RNA-seq) was performed in patients with chemotherapy-resistant AML and chemotherapy-sensitive AML. AML mRNA data from 151 patients with recurrence were downloaded from TCGA. Integrated analysis of the differentially expressed genes (DEGs), GO and KEGG pathways. CENPE, CENPF, or DLGAP5 knockdown cell lines were used to analyse proliferation, apoptosis and cell cycle alterations. RESULTS: A total of 87 DEGs (48 upregulated and 39 downregulated) were obtained through gene analysis of R/R-AML and a total of 329 DEGs (202 upregulated and 127 downregulated) were obtained in refractory S-AML. Upregulated DEGs were mainly enriched in cell cycle (GO: 0007049, hsa04110) and mitotic cell cycle (GO: 0000278) processes and pathway. Venn diagram analysis identified the most upregulated DEGs (including CENPE, CENPF, and DLGAP5) in chemoresistant AML. The expression of CENPE, CENPF and DLGAP5 in R-AML (TCGA) was significantly higher than that of primary AML (GEO). The proliferation of K562 cells after CENPE and DLGAP5 knockdown was significantly decreased (P= 0.0001 and P= 0.0006). In THP-1 cells, the CCK-8 values after CENPE, CENPF and DLGAP5 knockdown were significantly decreased (P= 0.01, P= 0.0395 and P= 0.0362). Knockdown of CENPE, CENPF and DLGAP5 significantly increased cell apoptosis by regulating Caspase-9, BAX, TP-53 and bcl-2, and induced cell cycle arrested by regulating CDK1, CDK2, CDKN1A, and CyclinD1. CONCLUSIONS: In conclusion, the mitotic cell cycle-associated genes CENPE, CENPF, and DLGAP5 were upregulated in chemotherapy-resistant AML patients and might be useful for predicting poor prognosis.

Background: Infections in patients with hematological malignancies (HM) are a significant cause of morbidity and mortality. Timely and effective empirical anti-infective treatment can reduce the infection-related mortality rate. Targeted next-generation sequencing (tNGS) offers a rapid diagnostic approach for identifying diverse pathogens in these patients. However, relevant research is still limited to adult patients with HM.Methods: We conducted a retrospective analysis of adult HM patients admitted to our hospital from March 2023 to September 2023, focusing on their clinical characteristics and the results of both tNGS and conventional microbiological tests (CMTs). We evaluated the performance of tNGS and CMTs in pathogenic diagnosis and described the distribution characteristics of pathogens in adult HM patients with infections.Results: The study included 209 samples collected from 137 patients. Results showed that the overall pathogen detection rate differed significantly between tNGS and CMTs (60.3% vs. 24.4%, p < 0.001). The sensitivity (69.7% vs. 35.9%), negative predictive value (NPV) (48.2% vs. 42.4%), and accuracy (66.5% vs. 56.5%) of pathogen detection were notably superior with tNGS compared to CMTs. Among the 142 samples with clinically diagnosed infections, tNGS combined with CMTs identified a definite or probable microbial etiology in 114 samples (80.3%). Of the 36 samples with concordant positive results from both tNGS and CMTs, 72.2% (26/36) exhibited full or partial agreement. Our study further showed the highest detection rate for viral infections (57.0%), predominantly for Epstein–Barr virus (DNA-V, 18.3%). Followed by bacterial infections (46.5%), the detection rate of Gram-negative bacteria (G⁺, 35.9%) was higher than that of Gram-positive bacteria (G⁻, 21.8%) in this study. Klebsiella pneumoniae (G⁻, 12.7%) had the highest detection rate among these emerging bacteria, followed by Pseudomonas aeruginosa (G⁻, 10.6%) and Enterococcus faecium (G⁺, 7.7%). Bacterial-viral coinfections were the most common type of mixed infection (35.5%).Conclusion: In conclusion, tNGS outperforms CMTs in both sensitivity and pathogen spectrum. Therefore, it can serve as an adjunct to CMTs to facilitate the precise adjustment of anti-infective regimens for adult HM patients. Our findings establish a basis for formulating empirical anti-infective therapy strategies tailored to the pathogen distribution in this patient population.

The prognosis of chemoresistant acute myeloid leukemia (AML) is still poor, mainly owing to the sustained proliferation ability of leukemic cells, while the microtubules have a major role in sustaining the continuity of cell cycle. In the present study, we have identified CENPE, a microtubular kinesin-like motor protein that is highly expressed in the peripheral blood of patients with chemoresistant AML. In our in vitro studies, knockdown of CENPE expression resulted in the suppression of proliferation of myeloid leukemia cells and reversal of cytarabine (Ara-C) chemoresistance. Furthermore, Lin28A, one of the RNA-binding oncogene proteins that increase cell proliferation and invasion and contribute to unfavorable treatment responses in certain malignancies, was found to be remarkably correlated with CENPE expression in chemoresistance AML. Overexpression of LIN28A promoted the proliferation and Ara-C chemoresistance of leukemic cells. RIP assay, RNA pull-down, and dual luciferase reporter analyses indicated that LIN28A bound specifically to the promoter region GGAGA of CENPE. In addition, the impacts of LIN28A on cell growth, apoptosis, cell cycle progression, and Ara-C chemoresistance were reverted by the knockdown of CENPE. Hence, Lin28A/CENPE has enhanced the proliferation and chemoresistance of AML, and therefore, it could be a prospective candidate for AML treatment.