KRAS::ETNK1 fusion found in MDS/MPN overlap syndrome case study

A Rare Genetic Signature in Myeloid Disease

In the complex world of hematology, where researchers often hunt for familiar mutations, occasionally a case emerges that defies the standard diagnostic rulebook. This case serves as a stark reminder of how much we still have to learn about the molecular machinery underlying rare blood cancers.

The patient, a 61-year-old man, initially presented to the Hematology Department at Lyon Sud Hospital in July 2024 with a constellation of symptoms that pointed toward a systemic issue: fatigue, low-grade fever, and persistent inflammatory arthralgias. Blood work revealed marked eosinophilia and circulating myeloid precursors. While the presence of mutations in genes like ASXL1, TET2, and EZH2 might seem familiar to clinicians, the underlying driver—a fusion between KRAS and ETNK1—was anything but.

The Mechanics of a Hidden Fusion

Standard diagnostic tools like karyotyping failed to detect the rearrangement. It took targeted RNA sequencing with a 1106-gene panel to uncover the fusion, which resulted from an inversion within chromosome 12p12. This specific genetic event joined KRAS exon 5 to ETNK1 exon 8. The resulting protein is structurally unique: it retains the Ras domain of KRAS and the kinase domain of ETNK1, but crucially, it loses the CAAX motif. This motif is typically responsible for anchoring KRAS to the cell membrane. By shedding this anchor, the fusion likely avoids classic RAS pathway activation, instead potentially driving the disease through metabolic reprogramming and oxidative stress.

This discovery underscores the limitations of relying solely on conventional testing. As the authors of the report note, this fusion expands our understanding of how ETNK1 alterations can contribute to myeloid neoplasms. Previously, recurrent ETNK1 mutations have been linked to atypical chronic myeloid leukemia, and research published in Nature Communications has suggested that these mutations can induce a mutator phenotype, which theoretically might be reverted by phosphoethanolamine treatment.

Clonal Evolution and the Limits of Transplant

The clinical trajectory of this patient highlights the brutal reality of clonal evolution in aggressive myeloid diseases. After undergoing two cycles of azacitidine and venetoclax, the patient proceeded to an allogeneic hematopoietic stem cell transplantation (HSCT) in November 2024. Initially, the results were promising: he achieved complete morphologic remission with nearly perfect donor chimerism. However, the victory was short-lived.

By the third month post-transplant, minimal residual disease had emerged, and within a few weeks, the patient relapsed with a high blast count. Whole-genome sequencing at the time of relapse painted a picture of a rapidly shifting landscape. The clones that had originally driven the disease—those carrying the KRAS::ETNK1 fusion—had vanished. In their place were new mutations in genes such as EP300, FAT1, GATA2, and MYB. The disease had essentially reinvented itself, evolving into secondary acute myeloid leukemia.

The association of this 12p deletion with relapse lacking MPN characteristics illustrates a mechanism of immune editing after transplantation, suggesting both the immune sensitivity of the KRAS::ETNK1 fusion transcript and its specific involvement in the MPN component of the disease.

The Unanswered Questions

Why did the fusion-bearing clone disappear? The researchers suggest that immune pressure following the transplant may have acted as a selective force, effectively pruning the original clone only for more aggressive, resistant sub-clones to take its place. Alternatively, therapy-driven selection or random genetic drift could have played a role. Because no diagnostic RNA remained from the relapse period, the team could not confirm the fusion’s mechanisms with a second method, leaving it as a singular, albeit highly informative, case study.

The patient’s death in July 2025 emphasizes the stakes for patients with these rare, overlapping syndromes. As we continue to refine our ability to map the genome of these malignancies, the focus must remain on the clinical utility of comprehensive molecular profiling. It is not enough to identify a mutation; we must understand the dynamic, often volatile way these clones respond to the high-pressure environment of a stem cell transplant. This case serves as a call for larger studies to determine if this KRAS::ETNK1 fusion is a rare anomaly or a recurring, albeit stealthy, driver in a subset of patients who currently fall through the cracks of standard diagnostics.