A 61-year-old male patient presenting with a myelodysplastic/myeloproliferative overlap syndrome was found to harbor a novel KRAS::ETNK1 fusion transcript, ajmc.com reported. Targeted RNA sequencing with a 1106-gene panel picked up the genetic alteration, which joined KRAS exon 5 to ETNK1 exon 8. Standard karyotyping failed to spot the anomaly, which researchers believe stems from an inversion within chromosome 12p12.
The predicted fusion protein retains the Ras domain of KRAS alongside the kinase domain of ETNK1. However, it drops the CAAX motif that normally tethers KRAS to the cell membrane. According to study authors cited by ajmc.com, this configuration makes classic RAS pathway activation unlikely. Instead, the fusion may drive disease through aberrant metabolic activity and oxidative stress.
Clinical Presentation at Lyon Sud Hospital
The patient sought care at the Hematology Department at Lyon Sud Hospital in early July 2024, pmc.ncbi.nlm.nih.gov reported. Symptoms began months earlier in February 2024, including fatigue, low-grade fever, oropharyngeal pain, cervical lymphadenopathy, headaches, and diffuse inflammatory arthralgias affecting the knees, right ring finger, and right wrist. Initial blood work revealed marked leukocytosis driven by eosinophilia, basophilia, and circulating myeloid precursors. Serum tryptase was elevated at 38.5 micrograms per liter.
Bone marrow examinations showed marked hypercellularity with megakaryocytic hyperplasia and dysmegakaryopoiesis. Targeted DNA sequencing at diagnosis also uncovered baseline mutations in several genes, including ASXL1, TET2, EZH2, BCOR, and SETBP1. The patient had a history of hypertension, osteoarthritis, and former smoking.
Patient undergoes stem cell transplant before relapsing
Treatment proceeded with two cycles of azacitidine combined with venetoclax, leaving 6% marrow blasts. In November 2024, the patient underwent an allogeneic hematopoietic stem cell transplantation from an HLA-matched unrelated donor. Initial post-transplant checks showed complete morphologic remission with 99.7% marrow donor chimerism at one month.
Minimal residual disease climbed to 1.5% by month three. By 3.5 months post-transplant, the patient relapsed with 20% to 35% marrow blasts. Whole-genome sequencing at the time of relapse revealed a chromosome 12p deletion, trisomy 8, and an acquired loss of heterozygosity on chromosome 7q.
Mutations shift dramatically as disease progresses
The clonal architecture shifted dramatically at the time of relapse. Clones carrying SETBP1, TET2, BRAF, or BCOR mutations vanished entirely. They were replaced by entirely new mutations involving EP300, FAT1, GATA2, and MYB.
The disappearance of the original fusion-bearing clone coincided with the chromosome 12p deletion. This shift illustrated how immune pressure or therapy-driven selection can alter leukemic evolution. Salvage therapy ultimately failed, and the patient died in July 2025.
Common Questions About the KRAS::ETNK1 Discovery
How was the KRAS::ETNK1 fusion identified if standard karyotyping missed it?
Researchers used targeted RNA sequencing equipped with a 1106-gene panel to detect the fusion transcript. Standard karyotyping could not visualize the underlying inversion within chromosome 12p12.
What happened to the original fusion-bearing clone after transplantation?
The clone disappeared following allogeneic stem cell transplantation alongside a chromosome 12p deletion. The disease subsequently evolved into secondary acute myeloid leukemia driven by entirely different molecular alterations.
What underlying mutations were present when the patient was first evaluated?
Initial diagnostic sequencing uncovered typical myelodysplastic/myeloproliferative overlap syndrome mutations, including alterations in ASXL1, TET2, EZH2, BCOR, and SETBP1.
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