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.

Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

Pioneer factors and chromatin modifications are pivotal in determining cell fate, yet their dynamics in disease contexts, particularly in vivo, remain incompletely understood. Our prior work (Wang et al., Nat Commun 2019) demonstrated that reprogramming factors selectively eliminate leukemia cells in vivo, with minimal effects on normal Hematopoietic Stem and Progenitor Cells (HSPCs), suggesting an influence of pre-existing chromatin states on induced cell fates.Building on this, we profiled pre-existing chromatin states in leukemia cells and HSPCs using MNase-ChIP-seq, ATAC-seq, and WGBS-seq. In our Tet-on-induced models, Klf4 activation resulted in the targeting of distinct gene sets and exhibited similar dynamic changes in chromatin accessibility, despite these regions sharing the same active chromatin state. Using machine learning algorithms, we found that H3K18ac is a key factor in Klf4 chromatin binding preferences. We altered H3K18ac via an enzymatically deficient SIRT7 and observed increased Klf4 binding at sites with elevated H3K18ac levels, suggesting H3K18ac influences Klf4 binding. We treated human CD34+ cells, various human leukemia cell lines, and leukemia patient samples with APTO-253, which elevates Klf4 expression and enhances its affinity for H3K18ac-rich sites, inducing apoptosis specifically in AML cells. Furthermore, co-treatment with 97491 dramatically reduces AML cell viability, while the population of CD34+ cells essentially remained stable, suggesting a synergistic therapeutic potential.In conclusion, our work demonstrated that pre-existing chromatin states, such as H3K18ac, regulate Klf4′s genomic binding, thereby influencing distinct cell fates in leukemia cells and HSPCs. These insights provide a basis for targeted AML therapies, underscoring the importance of integrating epigenetic and transcription factor analyses in cancer research.

To understand the molecular basis of heterogeneous hematopoietic stem cells (HSCs) is challenging. Especially, how a limited number of HSCs re-establish the HSC pool in myeloablated mice, and their molecular program regulating the reconstitution output remains elusive. Here, we tracked the clonal reconstitution by single-cell transplantation with single-cell RNA sequencing. Combining functional, immunophenotypical, and transcriptional assays, we found initial HSC clones expanded most significantly within a month and reached a plateau by 4 months, followed by gradual yet variable and fluctuated accumulation by 12 months after transplantation.Using hierarchical single-cell Bayesian model, the reconstitution and multilineage differentiation capabilities in single clones were evaluated during serial transplantation.There kinds of clones named Super, Flash, and Trickle were identified with distinct molecular features. Super HSC clones sustained higher level of multi-lineage reconstitution. Flash of lighting clones exhausted immediately after primary transplantation and exhibited a limited lymphoid-biased lineage output thereafter. Trickle clones continuously maintained low level of reconstitution.Super clone-derived HSCs were located on the apex of the hematopoietic hierarchty and specifically expressed genes involved in aerobic respiration, translation, and protein folding. To purify Super HSCs, we are currently testing candidate makers, for instance CD27 and CD74. Collectively, we revealed the establishment process of HSC compartment after transplantation and identified serially transplantable HSCs at the clonal level, providing promising target cells for in vivo and in vitro expansion of HSCs.

At present, all cell strains derived from acute lymphoblastic leukemia (ALL) patients with the long arm of chromosome 11 aberration are accompanied with mixed lineage leukemia (MLL) gene rearrangement. In this study, we established a permanent ALL cell strain CHH-1 with the long arm of chromosome 11 aberration and without MLL rearrangement, hoping that it could be used for the research of ALL with such genetic abnormality. CHH-1 cell strain was certified through morphology, immunophenotype, genetics and immunoglobulin (Ig) gene rearrangement analysis. Cell characteristics including tumorigenic ability, semisolid colony forming ability, telomerase activity, autocrine and invasion were further detected. Cells were with an add(11)(q23) structural abnormality without MLL rearrangement, and were consistent with the genetic abnormality of the patient. In addition, these cells had features of tumor-forming ability, high colony forming capacity, unique cytokine autocrine mode, high telomerase activity, and high invasion ability. CHH-1 may prove to be a useful cell model for the research of human leukemia with genetic aberration in chromosome 11, and help explore the role of such genetic abnormality in the pathogenesis, progression and prognosis of ALL, and in developing new target drugs.