血液科学(英文)最新文献

Chimeric antigen receptor (CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies, with 9 CAR-T-cell products currently available. Furthermore, CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune and infectious diseases. Despite these advancements, significant challenges pertaining to treatment-related toxic reactions and relapses persist. Consequently, current research efforts are focused on addressing these issues to enhance the safety and efficacy of CAR-T cells and reduce the relapse rate. This article provides a comprehensive overview of the present state of CAR-T-cell therapies, including their achievements, existing challenges, and potential future developments.

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse (P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.

A risk-adapted treatment strategy is of crucial importance in patients with myelodysplastic syndromes (MDS). Previous risk prognostic scoring systems did not integrate molecular abnormalities. The new IPSS-Molecular (IPSS-M) model, combing genomic profiling with hematologic and cytogenetic parameters, was recently developed to evaluate the associations with leukemia-free survival (LFS), leukemic transformation, and overall survival (OS). However, it has not yet been widely validated in clinics. This study aims to further validate the prognostic power of IPSS-M based on real-world data and to compare the prognostic value of different scoring systems in patients with MDS. IPSS-M Web calculator was used to calculate a tailored IPSS-M score of the enrolled patient (N = 255), and the risk category was defined correspondingly. We next compared the IPSS-M prognostic power to that of IPSS, IPSS-R, and WPSS. We found that IPSS-M risk classification was statistically significant for 3-year OS and LFS. Compared with other tools, IPSS-M was superior in sensitivity and accuracy for 3-year OS and LFS. The mapping C-index between IPSS-R and IPSS-M categories resulted in improved discrimination across the OS, but not LFS and leukemic transformation. The result of different treatment options indicated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) can result in a better OS than those without allo-HSCT. In conclusion, IPSS-M was a valuable tool for risk stratification compared with other risk prognostic scoring systems. However, more studies should be conducted to explore the appropriate treatment options for different groups stratified by IPSS-M.

MicroRNAs (MiRNAs) carried by exosomes play pivotal roles in the crosstalk between cell components in the tumor microenvironment. Our study aimed at identifying the expression profile of exosomal miRNAs (exo-miRNAs) in the serum of multiple myeloma (MM) patients and investigating the regulation networks and their potential functions by integrated bioinformatics analysis. Exosomes in serum from 19 newly diagnosed MM patients and 9 healthy donors were isolated and the miRNA profile was investigated by small RNA sequencing. Differential expression of exo-miRNAs was calculated and target genes of miRNAs were predicted. CytoHubba was applied to identify the hub miRNAs and core target genes. The LASSO Cox regression model was used to develop the prognostic model, and the ESTIMATE immune score was calculated to investigate the correlation between the model and immune status in MM patients. The top six hub differentially expressed serum exo-miRNAs were identified. 513 target genes of the six hub exo-miRNAs were confirmed to be differentially expressed in MM cells in the Zhan Myeloma microarray dataset. Functional enrichment analysis indicated that these target genes were mainly involved in mRNA splicing, cellular response to stress, and deubiquitination. 13 core exo-miRNA target genes were applied to create a novel prognostic signature to provide risk stratification for MM patients, which is associated with the immune microenvironment of MM patients. Our study comprehensively investigated the exo-miRNA profiles in MM patients. A novel prognostic signature was constructed to facilitate the risk stratification of MM patients with distinct outcomes.

Central nervous system leukemia (CNSL) is a prominent infiltration reason for therapy failing in acute leukemia. Recurrence rates and the prognosis have alleviated with current prophylactic regimens. However, the accurate stratification of relapse risk and treatment regimens for relapsed or refractory patients remain clinical challenges yet to be solved. Recently, with hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor-T (CAR-T) cellular therapy showing encouraging effects in some CNSL patients, advances in treating CNSL have already been reported. The development of molecular targeted agents as well as antibody-based drugs will provide patients with more personalized treatment. This article summarized recent research developments about risk factors, diagnosis, prevention, and treatment in adults with CNSL.

Matrix remodeling is a critical process in hematopoiesis. The biology of MXRA7, as a matrix remodeling associated gene, has still not been reported in hematopoietic process. Public databases showed that MXRA7 expressed in hematopoietic stem cells, suggesting that it may be involved in hematopoiesis. We found that the amounts of megakaryocytes were lower in bone marrow and spleen from Mxra7^-/- mice compared with that from wild-type mice. Knock-out of MXRA7 also reduced the amount of platelet in peripheral blood and affected the function of platelets. Knock-out of MXRA7 inhibited hematopoietic stem/progenitor cells differentiate to megakaryocytes possibly through down-regulating the expression of GATA-1 and FOG-1. Moreover, knockdown of MXRA7 in MEG-01 cells could inhibit the cell proliferation and cell apoptosis. Knockdown of MXRA7 inhibited the differentiation of MEG-01 cells and proplatelet formation through suppressing the ERK/MAPK signaling pathway and the expression of β-tubulin. In conclusion, the current study demonstrated the potential significance of MXRA7 in megakaryocyte differentiation and platelet production. The novel findings proposed a new target for the treatment of platelet-related diseases, and much more investigations are guaranteed to dissect the mechanisms of MXRA7 in megakaryocyte differentiation and platelet production.