Volume 08 · Issue 02 · 2026

Myelodysplastic syndrome (MDS) is a malignant clonal disorder originating from hematopoietic stem and progenitor cells and is characterized by ineffective hematopoiesis and a high propensity for transformation into acute leukemia. Research has indicated that the pathogenesis of MDS is closely linked to genetic mutations and that its progression may encompass multiple stages, including cytogenetic and molecular alterations, leading to the acquisition of oncogenic mutations. The widespread application of next-generation sequencing (NGS) technologies, including whole-genome sequencing, whole-exome sequencing, and RNA sequencing, has significantly improved our understanding of the genetic alterations and transcriptomic modifications underlying MDS. These technologies not only deepen our understanding of molecular mechanisms but also facilitate the identification of potential therapeutic targets and prognostic biomarkers. Consequently, the 2022 World Health Organization Classification and the International Consensus Classification have incorporated molecular features into the MDS classification system, and the Molecular International Prognostic Scoring System (IPSS-M) was introduced. This review aims to summarize the role of NGS in the precise diagnosis, classification, risk assessment, treatment selection, and evaluation of therapeutic effectiveness in MDS, with implications for advancing precision medicine in hematological malignancies.

Chimeric antigen receptor T (CAR-T) cell therapy has transformed hematologic cancer treatment; however, its application in patients with central nervous system (CNS) involvement remains challenging because of exclusion from key trials. Recent data show that CAR-T cells can breach the blood-brain barrier (BBB) and achieve clinically significant responses in CNS lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). However, limited CNS trafficking, antigen escape, an immunosuppressive microenvironment, and treatment-related neurotoxicity constrain therapeutic efficacy. This review synthesizes recent clinical outcomes, elucidates mechanisms of CNS infiltration and neurotoxicity, and evaluates emerging strategies, including optimized CAR designs, BBB-modulating technologies, alternative delivery routes, and rational combination therapies, to enhance safety and efficacy. Disease-specific nuances, such as Parkinson-like symptoms in CNS myeloma and differential neurotoxicity profiles between primary and secondary CNS lymphomas, are highlighted. By identifying key knowledge gaps and proposing prioritized research directions, this study aims to guide the future translation of CAR-T therapy for CNS hematologic malignancies.

Systematically interrogating the genetic regulators of long-term hematopoietic stem cell (HSC) function and their roles in malignant transformation in vivo remains a central challenge. We developed and validated a sequential in vivo CRISPR screening platform characterized by high sgRNA recovery after a 5-month reconstitution period and a pioneering pooled secondary transplantation strategy. This system not only identified enriched genes but also modeled the dynamics of clonal evolution. As a robust validation of our platform’s sensitivity, the screen identified Neurofibromin 1 (Nf1), a quintessential tumor suppressor, as the dominant hit using a focused transcription factor library. The primary screen recapitulated a myeloproliferative state. Strikingly, the secondary transplantation screen amplified this phenotype and led to malignant hematopoiesis. Thus, this 2-step approach establishes a powerful paradigm for studying the genetic drivers of long-term hematopoiesis and the evolutionary dynamics of hematological malignancies.

Marrow senescence contributes to overall organismal aging and involves functional alterations in both the mesenchymal and hematopoietic compartments of bone marrow. Although matrix remodeling-associated 7 (MXRA7) has been demonstrated to modulate mesenchymal function and megakaryocyte differentiation in mice, this study aimed to investigate the potential role of MXRA7 in marrow senescence. Single-cell RNA sequencing was performed on bone marrow cells from young and aged wild-type and MXRA7-knockout mice. Comparative analysis of 2-month-old and 2-year-old mice revealed that aging significantly altered the cellular proportions within the bone marrow niche, and MXRA7 deficiency markedly increased Macro1 macrophages in aged mice, likely driven by the dysregulation of the Ccl24-Ccr3 axis. MXRA7 deficiency altered Mid1 expression and the macrophage migration inhibitory factor (Cd74 + Cxcr4), Ccl6 + Ccr2, and Von Willebrand factor signaling pairs (Itga2b + Itgb3), all of which are closely associated with cell status in the bone marrow microenvironment. In summary, these findings underscore MXRA7’s role in cellular profile shifts during bone marrow aging, offering novel insights into how MXRA7 coordinates hematopoietic and immune homeostasis in the bone marrow.

Multidrug resistance (MDR) remains a major obstacle in the clinical treatment of leukemia, severely limiting therapeutic efficacy and leading to poor patient outcomes. Drug efflux mediated by ATP-binding cassette (ABC) transporters represents a central mechanism driving cancer MDR. In this study, we identified ABCB6 as a critical mediator of MDR in leukemia through its role in promoting drug efflux. Using membrane-focused liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the leukemia cell line K562 and its MDR derivative K562/A02, we screened for differentially expressed transporters and identified ABCB6 as a candidate molecule. We further confirmed that ABCB6 is abundantly expressed on the plasma membrane of K562/A02 cells. Functional analyses demonstrated that altered ABCB6 expression did not significantly affect cell proliferation or apoptosis; however, targeted knockdown of ABCB6 markedly restored the sensitivity of K562/A02 cells to adriamycin (ADR) and cytosine arabinoside (Ara-C). Mechanistic studies revealed that ABCB6 contributes to ADR efflux from leukemia cells, thereby reducing intracellular drug accumulation and weakening its cytotoxic activity. Together, these findings establish ABCB6 as a previously unrecognized efflux transporter that contributes to MDR in leukemia and highlight ABCB6 as a potential therapeutic target for overcoming MDR.

Acute myeloid leukemia (AML) is a hematological malignancy with a high mortality rate and heterogeneous prognosis. Traditional risk stratification is based on the genetic classification in the 2022 guidelines of the European Leukemia Net. However, the risks of some patients remain unclear, and other prognostic assessment methods are required to improve the risk assessment of these patients. Apoptosis-related genes (ARGs) play critical roles in regulating the survival and drug resistance of AML cells. Therefore, we collected gene expression and clinical data from patients with AML from The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA-LAML) datasets to develop a risk assessment model based on 5 ARGs. Using the least absolute shrinkage and selection operator Cox regression (LASSO-Cox) model, we identified 5 key ARGs (DDIT4, HSP90B1, ENO1, SOD1, and SLC7A11) and constructed a 5-ARG prognostic model. Using this model, we successfully stratified patients in both TCGA-LAML training and independent external validation cohorts, with high-risk patients consistently exhibiting significantly poorer clinical outcomes. In addition, high-risk patients exhibited significant enrichment in pathways related to TP53 dysfunction, mechanistic target of rapamycin complex 1 (mTORC1) signaling activation, and pro-inflammatory responses, which were closely correlated with NPM1c-FLT3 co-mutations. Decitabine, sunitinib, and MK-1775 were identified as potential therapeutic agents. In summary, we established a 5-ARG prognostic model that may facilitate risk stratification and inform therapeutic decision-making in AML.

Marginal zone lymphoma (MZL) is an indolent subtype of non-Hodgkin lymphoma with heterogeneous clinical features. First-line treatment typically involves anti-CD20 monoclonal antibodies with or without chemotherapy. Although Bruton’s tyrosine kinase (BTK) inhibitors have demonstrated efficacy in relapsed/refractory (R/R) MZL, their role as first-line therapy remains unclear. This single-center retrospective study included 25 treatment-naïve patients with MZL who received orelabrutinib (150 mg once daily) plus either rituximab or obinutuzumab for 6 cycles, followed by orelabrutinib maintenance for up to 6 months. The primary endpoint was overall response rate (ORR), assessed according to the 2014 Lugano criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The ORR was 96.0%, comprising 12 complete response (CR) and 12 partial response (PR), with 1 case of stable disease (SD). Among the 13 patients with ocular adnexal MZL (OAML), 5 achieved CR, and 8 achieved PR. In the rituximab subgroup (n = 10), 5 patients achieved CR and 5 achieved PR, whereas in the obinutuzumab subgroup (n = 15), 7 achieved CR, 7 achieved PR, and 1 had SD; there was no significant difference in CR rate between the 2 groups (50.0% vs 46.7%, p = 1.000). Treatment-related adverse events (AEs) occurred in 32.0% of patients, with neutropenia (20.0%) and thrombocytopenia (12.0%) being the most common. Grade 3 to 4 events occurred in 12.0% of patients, with no significant differences in safety profiles between the rituximab and obinutuzumab subgroups. In conclusion, CD20 monoclonal antibodies combined with orelabrutinib may represent a feasible, low-toxicity first-line option for MZL, with favorable short-term efficacy and tolerability observed in this cohort. These preliminary findings warrant confirmation in larger prospective randomized studies to establish long-term benefits and safety.

Anti-CD19 chimeric antigen receptor T cells (CAR T) still have many limitations, including insufficient clinical efficacy. Zanubrutinib is a second-generation Bruton tyrosine kinase (BTK) inhibitor with higher drug potency, and it is not clear whether it has an enhanced killing effect of CD19 CAR T on B-cell lymphoma. Therefore, this study will investigate the role and mechanism of zanubrutinib in CD19 CAR T therapy against B-cell lymphoma. B-cell lymphoma cells Daudi were proportionally co-cultured with CD19 CAR T and intervened using different concentrations of zanubrutinib, and the changes of cell viability, apoptosis, autophagy, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway-related factors were assessed using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Western blotting, transmission electron microscopy, and immunofluorescence staining. Also, the effect of zanubrutinib on the sensitivity of B-cell lymphoma mice to CAR T-cell therapy was observed. The results showed that zanubrutinib increased the sensitivity of B-cell lymphoma to CD19 CAR T-cells, promoted apoptosis and autophagy, and inhibited BTK phosphorylation and the PI3K/AKT/mTOR signaling pathway. Zanubrutinib can promote the killing of B-cell lymphoma by CD19 CAR T. Collectively, zanubrutinib enhances CD19 CAR T killing of B-cell lymphoma by inhibiting BTK phosphorylation, regulating PI3K/AKT/mTOR pathway, and promoting autophagy.

Acute myeloid leukemia (AML) is a subtype of hematopoietic neoplasm affecting myeloid cells in blood and bone marrow. Molecular subtyping of AML provides in-depth insights into disease pathogenesis, facilitating clinical diagnostics and therapeutic management. While current molecular screening is mainly established on DNA-based approaches, including targeted sequencing of gene panels and polymerase chain reaction (PCR)-based fusion gene detection, transcriptome-based RNA-seq has gained increasing attention for its potential in improving molecular subtyping as well as in facilitating prognostic prediction and therapeutic selection. In this study, we aimed to identify transcriptomic signatures in molecular genotyping and risk stratification in a cohort of 125 patients with AML excluding those harboring PML::RARA fusion genes. We subsequently established a 2-step diagnostic assay based on transcriptomic expression, which can be further explored for predicting the outcome of AML patients with increased confidence and accuracy. Together with the identification of genetic mutations and fusion genes, transcriptome-based stratification might significantly enhance the ability of outcome prediction. In summary, we developed a transcriptomics-based multi-omics prediction model for improved risk stratification of patients with AML.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in hematologic malignancies, yet its durability is limited by insufficient expansion, persistence, and T-cell exhaustion. Basic leucine zipper ATF-like transcription factor (BATF) promotes CD8+ T-cell effector differentiation but can drive exhaustion under chronic stimulation. Here, we developed a transient, non-viral strategy to modulate BATF expression in therapeutic T cells using clinically approved lipid nanoparticles (LNPs). Among 3 Food and Drug Administration (FDA)-approved ionizable lipids, SM-102-based LNPs achieved the highest mRNA delivery efficiency in primary T cells. Transient BATF overexpression enhanced T-cell cytotoxicity in vitro without inducing exhaustion. In vivo, BATF mRNA transfection enhanced T-cell expansion, reduced exhaustion, and improved anti-tumor activity for both OT-1 TCR-T cells in melanoma and CD19 CAR-T cells in acute lymphoblastic leukemia. These findings establish a safe and reversible platform for transient transcription factor modulation to optimize T-cell differentiation and function, thereby enhancing the efficacy of adoptive T-cell therapies and supporting clinical translation.