The acquired JAK2-V617F mutation plays a causal role in myeloproliferative neoplasms (MPN). Weakly activating JAK2 germline variants have been associated with MPN risk, but the underlying mechanisms remain unclear. We previously identified the JAK2-R1063H germline variant, which contributes to hereditary MPN and increased disease severity in essential thrombocythemia. Here, we studied alterations in hematopoiesis in Jak2-R1063H knock-in mice. The Jak2-R1063H mouse cohort exhibited increased mortality, stimulated thrombopoiesis and elevated D-dimers levels, indicative of thrombotic complications. Bone marrow analysis revealed myeloid bias, enhanced megakaryopoiesis and activation of inflammatory signaling. Transcriptional and functional assays of hematopoietic stem cells suggested their accelerated aging and functional decline. The Egr1 transcriptional network, including the Thbs1 gene, progressively increased in aging mice, reinforcing alterations initiated by Jak2/Stat signaling. In murine acute myelogenous leukemia models, the Jak2-R1063H cooperated with a driver oncogene in promoting leukemogenesis. Germline JAK2-R1063H was found in 10 of 200 MPN patients from local hematology centers, with a higher minor allele frequency compared to healthy controls. Patients harboring JAK2-R1063H variant exhibited an increased incidence of thrombotic complications and disease progression with shortened survival. In conclusion, our findings identify the JAK2-R1063H germline variant as a risk factor for MPN development, thrombotic complications, and leukemic transformation. Our study, which involves a mouse model and a cohort of 200 MPN patients, characterizes the JAK2-R1063H germline mutation as a risk factor for MPN development, thrombotic complications, and leukemic transformation. These findings may have important clinical implications for managing MPN patients carrying the JAK2-R1063H germline variant.

• Publication type
• Journal Article MeSH

BACKGROUND: Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear. METHODS: In this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients. RESULTS: Comparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity. CONCLUSIONS: Our findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.

• Keywords
• Bioinformatics, Biomarkers, Myelodysplastic neoplasms, Next-generation sequencing, Transposable elements, piRNA,
• Publication type
• Journal Article MeSH