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Incorporation of genomic determinants improves diagnostic accuracy of oligomonocytic chronic myelomonocytic leukemia

ABSTRACT: Recent updates to the monocyte count thresholds for diagnosing chronic myelomonocytic leukemia (CMML) have been implemented to recognize oligomonocytic CMML (OM-CMML) as an early stage within the CMML spectrum. However, the clinical validity of these changes remains uncertain without considering biological factors. In this study, we compared a large cohort of patients (N=911) with OM-CMML (n=249), CMML (n=359), and myelodysplastic syndromes (n=303) using unsupervised clustering to assess the role of genomic determinants in improving CMML diagnostic accuracy. Our findings show that CMML molecular signatures, characterized by biallelic TET2 mutations or SRSF2-TET2 co-mutations, are associated with a distinct transcriptome, monocytic bias, classical monocytosis, and progression to overt CMML in OM-CMML cases. By developing a weighted and reproducible model, we demonstrate that genomic features, combined with bone marrow monocyte frequencies, can reliably predict CMML progression in OM-CMML. These results support the integration of genomic determinants into the CMML diagnostic framework to enhance diagnostic accuracy and suggest that incorporation of our proposed clinic-ready diagnostic workflow into clinical practice might reliably identify early stage CMML with oligomonocytic features.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314218 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. Genome wide DNA methylation profiling of patients samples with various myeloid malignancies and diffrential levels of 5hmC.The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in bone marrow samples and occasionally peripheral blood samples. Samples included 28 control healthy bone marrows, 29 patients samples with low 5hmC levels (7 patients with wild-type TET2 and 22 mutant TET2) and 24 with high levels of 5hmC (22 with wild-type TET2 and 2 mutant TET2). Bisulphite converted DNA from 81 samples was hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

Project description:Chronic myelomonocytic leukemia (CMML) is a clonal malignancy characterized by overlapping myeloid dysplasia and proliferation with persisting monocytosis. Characteristic repartitioning of classical monocytes is now a supporting diagnostic criterion (WHO5), though its mechanistic basis remains unknown. While monocytes are the cardinal malignant cell type in CMML, as a stem cell neoplasm the disease clone comprises most lineages and differentiation stages including granulocytes. To investigate the pathogenic contribution of granulocytes in CMML maintenance and progression, we have performed molecular and functional characterization of CMML granulocytes. Compared with healthy age-matched controls, CMML granulocytes exhibited defective maturation with reduced granularity and phagocytic capacity. Transcriptome analysis revealed activation of pathways linked to proliferation, Myc activity and inflammation. Notably, RETN, which encodes inflammatory mediator Resistin, was upregulated 100-fold in CMML granulocytes; but not differentially expressed in CMML PBMNCs, sorted monocytes, or stem and progenitor cells compared to their healthy counterparts. Accordingly, Resistin protein levels were 10-fold higher in plasma from CMML patients and higher plasma Resistin levels correlate with poor overall survival. Remarkably, exposure of healthy monocytes to exogenous recombinant Resistin induced classical monocyte repartition, recapitulating the pattern seen in CMML, and inhibited macrophage differentiation. Transcriptome analysis of Resistin treated monocytes revealed that Resistin induces gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. We found SEMA4A to be a downstream target of Resisin and is overexpressed in CMML monocytes. Consistent with known roles for SEMA4A, CMML patients displayed higher percentage of T-regs and elevated Th2/Th1 ratio compared with healthy controls, apparently corresponding with associated Resistin levels. Furthermore, we demonstrated that Resistin directly induces the T-reg expansion and skews the Th2/Th1 ratio by binding to monocytes. In conclusion, we showed that immature granulocytes in CMML produce high levels of Resistin, which contributes to classical monocytosis phenotype and immune suppression.

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Incorporation of genomic determinants improves diagnostic accuracy of oligomonocytic chronic myelomonocytic leukemia

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