Volume 05 · Issue 04 · 2023

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。¹然而，CD7-CAR-T细胞接受者总是免疫有希望，原因有很多：健康T和NK细胞的耗竭；在CAR-T细胞疗法之前需要淋巴细胞清除药物；血液恶性肿瘤病史；多线化疗；和造血干细胞移植(HSCT)。同时，考虑到同种异体细胞输注和感染发生率增加，供体来源的CAR-T细胞治疗后的患者处于移植物抗宿主病(GVHD)的高风险中。^2,3,4,5

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。¹我们报告了一例异基因造血干细胞移植（allo-HSCT）后表现为白血病孤立性髓外复发（IEMR）的心包积液病例。

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。¹GVHD靶组织在不同患者中是可变的，并且可以涉及胃肠道(GI)、肝、肺、皮肤、脾、淋巴结、胸腺和骨髓(BM)。²尽管急性GVHD的主要器官是胃肠道、肝脏和肺，但BM GVHD可延迟淋巴造血细胞的重建，导致随后的出血和感染，占Allo-HCT后死亡的约30%。³BM GVHD的发病机制被认为是供体CD4对BM基质小生境的破坏⁺Fas/FasL依赖性T细胞和供体CD4的耗竭⁺T细胞有效预防BM GVHD。^3,4除了直接抑制原始供体造血干细胞（HSCs）和阻断巨核细胞分化外，⁵来自供体T细胞的细胞因子(即GM-CSF、IFN-γ和TNF-α)也抑制HSC分化为对免疫耐受很重要的调节性浆细胞样树突状细胞(DC)。⁶然而，骨髓GVHD如何影响宿主型基质生态位及其与HSC的相互作用仍不清楚，林等人最近在JCI发表的一篇文章提供了新的见解。⁷