Year: 2025
Type: article
Study design: Case Report
Abstract: Background and Aims: JMML is driven by hyperactive Ras pathway signaling.Monosomy 7 (-7) occurs in ~25% of JMML cases and is assumed to be secondary to Ras pathway mutations.Here, we describe the unique clonal architecture in two children with JMML diagnosed at 13 (P1) and 6 (P2) months of age, in whom -7 preceded the KRAS mutation.Methods: We performed single cell DNA and protein sequencing (scDNAseq) using Mission Bio platform on serial samples of P1 and P2 with somatic KRAS mutation and -7.Bulk NGS and ddPPCR confirmed scDNAseq findings.Results: Analysis of 27.315 cells from five BM samples (P1: n=3, P2: n=2) revealed -7 as the founder clone with subsequent KRAS acquisition (P and P2 diagnostic samples: -7 only in 1.8% and 0.9%, -7/ KRAS in 37.7% and 41.5%, respectively).In P1, azacytidine therapy led to elimination of the JMML clinical phenotype, disappearance of the -7/KRAS clone (0%) and decrease of the -7-only clone (0.4%).Hematopoietic stem cell transplantation was performed for -7-only expansion (7%) and persistent severe neutropenia.P2 had stable disease under azacitidine therapy, an expanding -7/KRAS clonal burden (66.8%) and an unchanged -7-only clone (0.8%).Azacytidine therapy was associated with depletion of B cell and mature myeloid compartments in both patients.In P1, it promoted an 8-fold Treg expansion and increased CD4+ proportion; these changes were absent in P2.In both patients, a strong erythroblast bias emerged compared to diagnosis, suggesting either skewed differentiation or selective azacitidine resistance in myeloid/lymphoid lineages.Conclusions: Through single-cell analysis, we characterize the clonal architecture with monosomy 7 as initiating lesion in two patients with KRAS-mutant JMML.Furthermore, we provide first insights into azacitidine driven changes of clonal architecture.
Source: EJC Paediatric Oncology
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,340
OpenAlex ID: W4415903259