Case Report: Myelodysplastic/myeloproliferative neoplasm with concurrent SF3B1, ASXL1, JAK2 and CBL mutations and <15% bone marrow ringed sideroblasts

Abstract

This first-reported case of SF3B1-mutated myelodysplastic/myeloproliferative neoplasm with thrombocytosis (MDS/MPN-SF3B1-T), harboring coexisting ASXL1, JAK2 p.R683G, and CBL mutations challenges conventional genomic prognostic paradigms. A 72-year-old woman presented with anemia (Hb 91 g/L), thrombocytosis (Platelets 502×10⁹/L), and 10% bone marrow ring sideroblasts, fulfilling 2022 WHO diagnostic criteria through molecular precedence of SF3B1 p.K700E (VAF 40.5%) despite subthreshold sideroblasts. Comprehensive genomic profiling revealed a unique quadruple mutation signature: ASXL1 p.G646Wfs*12 (9.8% VAF), JAK2 p.R683G (17.5%), and CBL p.R149Q (16.2%), with preserved karyotype. Functional analyses demonstrated mutation-specific pathobiological crosstalk: 1) SF3B1-mediated mitochondrial iron mislocalization (ALAS2 splicing defects, ABCB7 downregulation) synergized with ASXL1-driven epigenetic repression of erythroid transcription factors (GATA1, KLF1), exacerbating anemia; 2) JAK2 p.R683G's partial kinase activation combined with CBL-dependent RAS/MAPK signaling sustained thrombocytosis through megakaryocytic hyperplasia. Despite harboring high-risk ASXL1 truncation, the patient maintained hematologic stability for six months without therapy, exhibiting declining platelet counts and improving Hb. This apparent genotype-phenotype discordance was attributed to clonal equilibrium (SF3B1 dominance suppressing ASXL1 leukemogenicity) and mutation-specific signaling attenuation (JAK2 R683G's suboptimal kinase activation). Our findings necessitate revision of therapeutic algorithms for molecularly complex, treatment-naive elderly patients, particularly in resource-limited settings where socioeconomic factors critically influence management strategies.

Keywords: <15% bone marrow ringed sideroblasts; JAK2 mutation; SF3B1 mutation; WHO classification criteria; myelodysplastic/myeloproliferative neoplasm (MDS/MPN).

Figure 1

(A–D) Bone marrow cytomorphology analysis. Bone marrow aspirate morphology demonstrated a moderately hypercellular marrow with notable megakaryocytic hyperplasia and platelet aggregates, consistent with thrombocytosis.

Figure 2

Mutation profile comparison. Comparative analysis of variant allele frequencies (VAFs) for SF3B1, ASXL1, JAK2, and CBL mutations.

Figure 3

Hematologic parameter trends. Longitudinal trajectory of hemoglobin (Hb), red blood cells (RBCs), white blood cells (WBCs), and platelet counts during initial diagnosis and follow-up monitoring. Gray dashed lines indicate reference thresholds for normal ranges.

Figure 4

SF3B1 clonal dominance modulates ASXL1/JAK2/CBL interplay in MDS/MPN-SF3B1-T. This schematic illustrates the molecular interplay underlying the paradoxical hematologic stability observed in this unique case of SF3B1-mutant MDS/MPN. The dominant SF3B1 p.K700E clone (VAF 40.5%) orchestrates a dual pathogenic cascade: while its spliceosomal dysfunction (via ABCB7/ALAS2 mis-splicing) drives ineffective erythropoiesis, it simultaneously attenuates the leukemogenic potential of the subclonal ASXL1 truncation through erythroid lineage restriction. Concurrently, the JAK2 p.R683G variant exhibits suboptimal kinase activation, which - when coupled with CBL p.R149Q-mediated RAS/MAPK hyperactivation and compensatory JAK2 ubiquitination - generates self-limiting thrombopoiesis. This intricate mutational synergy creates a state of clonal equilibrium, wherein competing oncogenic signals paradoxically maintain disease stability without therapeutic intervention, challenging conventional risk stratification paradigms.