Wang, Sa A

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.

ABSTRACT The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS‐related AML (AML‐MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi‐institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS‐related cytogenetics, BCR::ABL1 , KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL‐ RUNX1 and AML‐ RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS‐associated genes. No ALAL‐ RUNX1 or AML‐ RUNX1 cases showed concomitant TP53 mutation. ALAL‐ RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML‐directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL‐ RUNX1; however, it did not reach significance. Our results suggest ALAL‐ RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML‐ RUNX1 . Our findings suggest, like other MR mutations, RUNX1 ‐mutated ALALs should be included within AML‐MR.