Therapy resistance remains a major cause of relapse and poor outcomes in acute lymphoblastic leukemia (ALL). Recent multi-omics studies in ALL have revealed that resistance arises from a combination of leukemia-specific genetic lesions, treatment-driven clonal evolution, and adaptive non-genetic programs. Genomic analyses have identified recurrent alterations associated with resistance to chemotherapy, tyrosine kinase inhibitors, and immunotherapies, while single-cell profiling has uncovered heterogeneous cell states that persist during treatment and contribute to minimal residual disease. Emerging epigenetic, proteomic, and metabolic data further indicate that reversible regulatory and signaling changes play a central role in leukemic persistence. Integrative analyses are beginning to define convergent resistance pathways and clinically relevant biomarkers, although longitudinal sampling and clinical translation remain limited. This review summarizes the current multi-omics landscape of therapy resistance in ALL and discusses opportunities to improve risk stratification and therapeutic strategies.

Aims: To investigate DNA methylation patterns in early and terminal stages of erythropoiesis, and to explore the function of differentially methylated genes in erythropoiesis and erythroid disorder... Tweetable abstract DNAJA4 is a novel regulator of terminal erythropoiesis which is regulated by DNA methylation, and its dysregulated expression is closely associated with impaired erythropoiesis i...

Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that can modulate cellular metabolism, epigenetic modification, and redox homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be associated with pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains unclear. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We found that knockdown IDH1 induced chromatin reorganization and subsequently led to abnormalities biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of α-ketoglutarate (α-KG).We further revealed that knockdown IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq, and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies.

Lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) or exogenous lactate Na-La to decrease or increase intracellular lactate levels. The results showed the inhibition of glycolysis promoted erythroid progenitors’ differentiation, blocked cell cycle, and reduced colony formation of colony-forming unit-erythroid (CFU-E), whereas elevated lactate levels delayed erythroid progenitors’ differentiation and promoted CFU-E colony formation. We also found lactate levels directly regulated H3K14la intensity. Furthermore, we showed changes in H3K14la abundance and gene expression of the cell cycle and division-related genes CCNB1, CFL1, CENPA, and GNAI2, which were associated with stem cell pluripotency and differentiation. In conclusion, our study reveals lactate affects cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.

N ⁶ -methyladenosine (m ⁶ A) is a prevalent modification of mammalian mRNA. Increasing evidence has documented diverse roles of m ⁶ A in normal cell physiology and diseases. However, its functional role in erythropoiesis remains poorly understood. In this study, we found that deletion of Mettl3 using the EpoR-Cre mouse led to microcytic/hypochromic anemia due to defective erythropoiesis along with impaired hemoglobin biosynthesis. Mechanically, Mettl3 deficiency disrupted nucleotide biosynthesis, which induced DNA damage, leading to apoptosis of colony-forming unit–erythroid cells and cell-cycle arrest of erythroblasts. Integrated m ⁶ A-seq and RNA-seq analysis along with biochemical studies identified Mthfd1, a key enzyme involved in nucleotide biosynthesis, as a Mettl3 direct target gene. Furthermore, deletion of Mettl3 led to decreased expression of Mthfd1 , accompanied by a shortage of nucleotides deoxythymidine monophosphate and inosine monophosphate, in erythroid cells. Additionally, inhibition of METTL3 in human erythroid cells led to similar phenotypic and molecular changes, indicating a conserved role of METTL3 in human and murine erythropoiesis. Our findings have identified an METTL3-m ⁶ A- MTHFD1 axis that plays a critical role in erythropoiesis by maintaining genome stability of erythroid cells via regulation of nucleotide biosynthesis. These findings provide important insights into the regulatory mechanisms of erythropoiesis and may have implications for underlying the mechanisms of anemias.