MedNexus
2023年 · 第05卷第04期
MedNexus
Multiple myeloma (MM) is a malignant neoplasm characterized by clonal proliferation of abnormal plasma cells. In many countries, it ranks as the second most prevalent malignant neoplasm of the hematopoietic system. Although treatment methods for MM have been continuously improved and the survival of patients has been dramatically prolonged, MM remains an incurable disease with a high probability of recurrence. As such, there are still many challenges to be addressed. One promising approach is single-cell RNA sequencing (scRNA-seq), which can elucidate the transcriptome heterogeneity of individual cells and reveal previously unknown cell types or states in complex tissues. In this review, we outlined the experimental workflow of scRNA-seq in MM, listed some commonly used scRNA-seq platforms and analytical tools. In addition, with the advent of scRNA-seq, many studies have made new progress in the key molecular mechanisms during MM clonal evolution, cell interactions and molecular regulation in the microenvironment, and drug resistance mechanisms in target therapy. We summarized the main findings and sequencing platforms for applying scRNA-seq to MM research and proposed broad directions for targeted therapies based on these findings.
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.
CD7是T细胞急性淋巴细胞白血病（T-ALL）的理想嵌合抗原受体（CAR）靶点。供体来源的CAR-T细胞疗法作为一种新兴的治疗策略，在难治性/复发性（r/r）T-ALL中表现出优异的疗效，完全缓解（CR）超过90%，为改善预后和生存质量带来了新的希望，并为后续桥接移植提供了更多机会。
髓外白血病浸润可作为复发的表现。然而，它是罕见的，文献中报告的心血管复发不到10例，它经常表现为髓样肉瘤。
同种异体造血细胞移植（Allo-HCT）由于同种异体反应性供体T细胞介导的移植物抗白血病/淋巴瘤（GVL）活性而成为血液恶性肿瘤的治愈疗法，但是由供体T细胞介导的移植物抗宿主病（GVHD）仍然是Allo-HCT广泛临床应用的主要障碍。
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