KRAS::ETNK1 Fusion Identified in MDS/MPN Overlap With Eosinophilia

A man with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome and eosinophilia carried a previously unreported KRAS::ETNK1 fusion transcript that was no longer detectable after allogeneic hematopoietic stem cell transplantation (HSCT), when his disease returned as secondary acute myeloid leukemia, according to a case report published in eJHaem.¹ The authors, from Hospices Civils de Lyon in France, believe it is the first MDS/MPN case reported with the fusion.

At relapse, a new deletion on chromosome 12p covering both genes accounted for the fusion’s loss, and the leukemia had shed its myeloproliferative features. The investigators read that as a possible sign of immune editing after transplant, though they acknowledged their data could not show immune recognition of the fusion itself.

ETNK1 Alterations in MDS/MPN Overlap Syndromes

MDS/MPN overlap syndromes are rare clonal blood cancers with both dysplastic and proliferative features, and outside of allogeneic transplant they tend to show poor treatment responses.² Somatic ETNK1 mutations were first reported in 2015 in 6 of 68 (8.8%) samples of atypical chronic myeloid leukemia, an MDS/MPN subtype.³ Later work linked them to lower phosphoethanolamine levels, mitochondrial overactivity, DNA damage, and the buildup of new mutations.⁴

The patient, a 61-year-old man, was referred to Lyon Sud Hospital in July 2024 after 5 months of fatigue, fever, lymph node swelling, and joint pain.¹ Blood counts showed eosinophilia and basophilia, serum tryptase was elevated at 38.5 µg/L, and a hypercellular marrow with megakaryocytic hyperplasia, increased mast cells, and grade 1 fibrosis supported an MDS/MPN diagnosis. Testing was negative for BCR::ABL1, ETV6::PDGFRB, and FIP1L1::PDGFRA fusions and for JAK2 V617F and KIT D816V mutations.

How the KRAS::ETNK1 Fusion Was Detected

Targeted DNA sequencing found mutations in genes including ASXL1, BCOR, EZH2, SETBP1, and TET2, and targeted RNA sequencing with a 1106-gene panel picked up the fusion. It joined KRAS exon 5 to ETNK1 exon 8, likely through an inversion within 12p12 that standard karyotyping could not see. The predicted protein keeps the Ras domain of KRAS and the kinase domain of ETNK1 but drops the CAAX motif that anchors KRAS to the cell membrane.

“Such a configuration makes constitutive KRAS signaling unlikely, but could instead promote aberrant metabolic activity through an ETNK1-like kinase expressed under KRAS regulatory control,” the authors wrote. They proposed that the fusion may act through metabolic reprogramming and oxidative stress rather than classic RAS pathway activation.

Clonal Evolution After Allogeneic Transplant

After 2 cycles of azacitidine plus venetoclax (Venclexta; AbbVie/Genentech), 6% marrow blasts remained, and the patient underwent HSCT from an HLA-matched unrelated donor in November 2024. He reached complete morphologic remission with 99.7% marrow donor chimerism at 1 month, but minimal residual disease of 1.5% appeared by month 3, and at 3.5 months he relapsed with 20% to 35% marrow blasts.

Whole-genome sequencing at relapse showed the 12p deletion, trisomy 8, and acquired loss of heterozygosity on 7q. Clones carrying SETBP1, TET2, BRAF, or BCOR mutations had disappeared, replaced by new EP300, FAT1, GATA2, and MYB mutations. Salvage therapy failed, and the patient died in July 2025.

As a single case, the report cannot establish what the fusion does in disease, and the authors could not confirm it with a second method because no diagnostic RNA remained. They also noted other explanations for the fusion’s loss besides alloimmune pressure, including therapy-driven selection, random drift, and expansion of a subclone that lacked the fusion. The authors called for additional cases and functional studies to clarify the fusion’s role in leukemogenesis.

“[T]his case expands the spectrum of ETNK1 alterations in myeloid neoplasms by reporting a novel KRAS::ETNK1 fusion and illustrates substantial clonal evolution after allogeneic transplantation, highlighting the importance of comprehensive molecular profiling in MDS/MPN,” the authors concluded.

References

1. Caledec M, Labussière-Wallet H, Fontaine J, et al. Identification of a novel KRAS::ETNK1 fusion transcript in a myelodysplastic/myeloproliferative overlap syndrome with eosinophilia: a case report. EJHaem. 2026;7(6):e70450. doi:10.1002/jha2.70450

2. Kuendgen A, Kasprzak A, Germing U. Hybrid or mixed myelodysplastic/myeloproliferative disorders – epidemiological features and overview. Front Oncol. 2021;11:778741. doi:10.3389/fonc.2021.778741

3. Gambacorti-Passerini CB, Donadoni C, Parmiani A, et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood. 2015;125(3):499-503. doi:10.1182/blood-2014-06-579466

4. Fontana D, Mauri M, Renso R, et al. ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine. Nat Commun. 2020;11(1):5938. doi:10.1038/s41467-020-19721-w