2024年 · 第06卷第04期

循环系统是一个复杂的网络，是营养分配、废物清除和免疫防御的生命线。在其核心，血液生态系统是一个动态和微调的环境，其中不同的细胞成分共存并相互作用以维持体内平衡。

Hematopoietic stem cells (HSCs) maintain homeostasis in the hematopoietic ecosystem, which is tightly regulated at multiple layers. Acute myeloid leukemia (AML) is a severe hematologic malignancy driven by genetic and epigenetic changes that lead to the transformation of leukemia stem cells (LSCs). Since somatic mutations in DNA methylation-related genes frequently occur in AML, DNA methylation is widely altered and functions as a starting engine for initiating AML. Additionally, RNA modifications, especially N⁶-methyladenosine (m⁶A), also play an important role in the generation and maintenance of the hematopoietic ecosystem, and AML development requires reprogramming of m⁶A modifications to facilitate cells with hallmarks of cancer. Given the complex pathogenesis and poor prognosis of AML, it is important to fully understand its pathogenesis. Here, we mainly focus on DNA methylation and RNA m⁶A modification in hematopoiesis and AML and summarize recent advances in this field.

Accumulated evidence emerges that dynamic changes in human gut microbiota and microbial metabolites can alter the ecological balance of symbiotic hosts. The gut microbiota plays a role in various diseases through different mechanisms. More and more attention has been paid to the effects that human microbiota extends beyond the gut. This review summarized the current understanding of the roles that gut microbiota plays in hematopoietic regulation and the occurrence and development of benign and malignant hematologic diseases. The progress of the application of microbiota in treatment was discussed in order to provide new insights into clinical diagnosis and treatment in the future.

Megakaryocytes (MKs) constitute a small portion of bone marrow cells and are primarily responsible for producing platelets, which are essential for hemostasis and wound healing. Recent studies have revealed that MKs and platelets perform diverse functions in various physiological and pathological contexts. This comprehensive review highlights the functional diversity of MKs beyond thrombopoiesis, including their roles in regulating hematopoietic stem cells, modulating immune responses, contributing to hematological malignancies, and influencing aging processes.

Hematopoietic stem progenitor cells (HSPCs) are derived from a specialized subset of endothelial cells named hemogenic endothelial cells (HECs) via a process of endothelial-to-hematopoietic transition during embryogenesis. Recently, with the usage of multiple single-cell technologies and advanced genetic lineage tracing techniques, namely, "TIF" approaches that combining transcriptome, immunophenotype and function/fate analyses, massive new insights have been achieved regarding the cellular and molecular evolution underlying the emergence of HSPCs from embryonic vascular beds. In this review, we focus on the most recent advances in the enrichment markers, functional characteristics, developmental paths, molecular controls, and the embryonic site-relevance of the key intermediate cell populations bridging embryonic vascular and hematopoietic systems, namely HECs and pre-hematopoietic stem cells, the immediate progenies of some HECs, in mouse and human embryos. Specifically, using expression analyses at both transcriptional and protein levels and especially efficient functional assays, we propose that the onset of Kit expression is at the HEC stage, which has previously been controversial.

The zinc finger transcription factor B-cell CLL/lymphoma 11B gene (BCL11B, CTIP2) plays a crucial role in T-cell development, but its role in T-cell malignancies has not yet been definitively clarified. In the literature, 2 contradictory hypotheses on the function of BCL11B exist. One suggests that BCL11B functions as tumor suppressor gene, and the other suggests that BCL11B functions as oncogene. The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies, confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach, based on recent findings of the function of BCL11B in DNA damage repair. Decreased BCL11B expression, resulting in deficient DNA repair, may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements, thereby leading to malignant transformation. On the other hand, decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells. We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it. In those cases, targeted inhibition of BCL11B expression may have a therapeutic effect. The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells (ITNK). Therefore, there is an urgent need to develop a specific BCL11B inhibitor.

Beyond its core role in iron metabolism, erythroferrone (ERFE) has emerged as a key player with far-reaching implications in various hematologic disorders. Its regulatory effect on hepcidin underlines its significance in conditions characterized by disrupted iron homeostasis. In β-thalassemia and myelodysplastic syndromes, its dysregulation intricately contributes to the clinical challenges of anemia and iron overload which highlights its potential as a therapeutic target. In anemia of chronic disease and iron deficiency anemia, ERFE presents a unique profile. In chronic kidney disease (CKD), the intricate interplay between ERFE, erythropoietin, and hepcidin undergoes dysregulation, contributing to the complex iron imbalance characteristic of this condition. Recent research suggests that ERFE plays a multifaceted role in restoring iron balance in CKD, beyond simply suppressing hepcidin production. The potential to modulate ERFE activity offers a novel approach to treating a spectrum of disorders associated with iron dysregulation. As our understanding of ERFE continues to evolve, it is poised to become a key focus in the development of targeted treatments, making it an exciting and dynamic area of ongoing research. Modulating ERFE activity presents a groundbreaking approach to treat iron dysregulation in conditions like iron deficiency anemia, thalassemia, and hemochromatosis. As new research unveils its intricate roles, ERFE has rapidly emerged as a key target for developing targeted therapies like ERFE agonists and antagonists. With promising studies underway, this dynamic field holds immense potential to improve patient outcomes, reduce complications, and offer personalized treatment options in hematology research. This comprehensive overview of ERFE’s role across various conditions underscores its pivotal function in iron metabolism and associated pathologies.

Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations, and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukemia. However, these sequencing-based studies mainly focus on nuclear DNAs. Increasing evidence indicates that mitochondrial dysfunction is an important mechanism of leukemia pathogenesis, which is closely related to the mitochondrial genome variations. Here, we provide an overview of current research progress concerning mitochondrial genetic variations in leukemia, encompassing gene mutations and copy number variations. We also summarize currently accessible mitochondrial DNA (mtDNA) sequencing methods. Notably, somatic mtDNA mutations may serve as natural genetic barcodes for lineage tracing and longitudinal assessment of clonal dynamics. Collectively, these findings enhance our understanding of leukemia pathogenesis and foster the identification of novel therapeutic targets and interventions.

We aimed to identify dynamic changes of lysine (K)-specific methyltransferase 2A partial tandem duplications (KMT2A-PTD) before and after haploidentical donor hematopoietic stem cell transplantation (HID HSCT) and explore the prognostic value of pre-transplantation levels of KMT2A-PTD in acute myeloid leukemia (AML) receiving HID HSCT. Consecutive 64 AML patients with KMT2A-PTD positivity at diagnosis receiving HID HSCT were included in this study. Patients with KMT2A-PTD ≥1% before HSCT had a slower decrease of KMT2A-PTD after HID HSCT. Patients with KMT2A-PTD ≥1 % before HID HSCT had a higher cumulative incidence of relapse (36.4%, 95% confidence interval [CI]: 6.3%-66.5%) at 2 years after HSCT than those with KMT2A-PTD <1 % (7.5%, 95% CI: 0.3%-14.7%, P = 0.010). In multivariable analysis, KMT2A-PTD ≥1% before HID HSCT was the only independent risk factor for relapse (hazard ratio [HR]: 4.90; 95% CI: 1.22-19.59; P = 0.025). Thus, pre-transplantation levels of KMT2A-PTD could predict relapse in AML patients following HID HSCT.

现在已经很好地确定巨核细胞生成有两种不同的途径。一种是由传统的逐步分化途径定义的，其从造血干细胞和祖细胞(HSPC)进展到普通骨髓祖细胞(CMP)、巨核细胞-红系祖细胞(MEP)、巨核细胞祖细胞(MKP)，然后到产生血小板的巨核细胞(MK)。^1,2另一种途径最近被报道为从HSPCs到MkPs的直接分化途径^3,4(图1A).李等人最近的研究⁵已经揭示了这两种途径对炎症和清髓应激源的反应不同，除了产生血小板的MK之外，还分别产生炎症或支持小生境的MK。⁵

嵌合抗原受体（CAR）T细胞疗法代表了癌症治疗的突破性进展，目前美国食品药品监督管理局（FDA）批准的6种产品就证明了这一点。尽管其在治疗某些类型的血液癌症方面取得了成功，但该疗法与已知的局限性相关，包括潜在的显著副作用、T细胞无法穿透实体瘤以及由于抑制性肿瘤微环境(TME)导致的细胞耗竭和抗肿瘤活性丧失。¹

卡罗林斯卡学院诺贝尔大会将2024年诺贝尔生理学或医学奖联合授予Victor Ambros和Gary Ruvkun，“以表彰他们发现了miRNA及其在转录后基因调控中的作用”。

免疫疗法，特别是免疫检查点阻断(ICB)疗法，是肿瘤学中有前途的治疗方式，其涉及增强免疫系统的肿瘤攻击能力。几项临床前和临床研究强调了ICB在恶性肿瘤中的转化潜力。¹然而，ICB疗法的功效通常受到实体瘤中固有和获得性耐药机制的阻碍，这通常是由于肿瘤新抗原、检查点靶标和细胞毒性T淋巴细胞的炎性存在的缺乏。²肿瘤微环境（TME）具有深刻的免疫抑制作用，是ICB治疗临床疗效有限的关键原因。在这种环境中，肿瘤相关巨噬细胞(TAM)是主要的髓样细胞亚群，它们的高浸润水平与介导对ICB治疗的耐药性有关，从而与一系列癌症的不良预后相关。³中报告的最新进展自然癌症阐明了有助于促进肿瘤免疫逃避和对ICB治疗的耐药性的特定TAM亚群。最近的两项研究描述了SIRP α的作用⁺结直肠癌（CRC）中的TAMs⁴和Siglec-9⁺多形性胶质母细胞瘤(GBM)中的TAMs，⁵分别地。这些研究表明，靶向消融实体瘤中这些关键的免疫抑制亚群可能导致re的编程t幽默我免疫米icro-和环境，称为重定时从而潜在地增强免疫疗法的功效。这种调节时间的靶向方法可能提供一种新的策略来克服ICB耐药性造成的障碍，从而增强癌症患者免疫治疗的临床益处。

新出现的证据表明，老年多发性骨髓瘤（MM）患者的健康/虚弱状态是高度动态的，受衰老、疾病进展和治疗等因素的影响。这强调了治疗决策不仅基于初始健康/虚弱评估，而且基于其在治疗过程中的变化的重要性。在这方面，张等人¹据我们所知，最近报道了第一项针对表现出各种健康/虚弱状态的新诊断MM（NDMM）老年患者的个体化动态虚弱定制治疗（DynaFiT）的前瞻性研究。