Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

SIMPLE SUMMARY: Myeloid neoplasms (MN) are malignant hematopoietic stem cell disorders, which can progress into aggressive forms of blood cancer, likely due to the acquisition of additional genetic alterations. We investigated bone marrow biopsies of MN patients who underwent progression and compared them to a cohort with stable disease course. We identified certain mutations that promote an unfavorable outcome and found that patients with a known progress harbor more genetic alterations in their MN than those who do not deteriorate. Furthermore, we underpinned the hypothesis that not only the sum of genetic alterations but also the order in which they appear matters in disease evolution. Our findings emphasize the importance of genetic testing in MN patients in order to assess their risk of progression into aggressive blood cancer. ABSTRACT: Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations—apart from the initial driver mutations—that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (ASXL1, DNMT3A, NRAS, SRSF2 and TP53) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. TET2 mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases (“TET2-first”), whereas two stable cases displayed a TET2-positive subclone (“TET2-second”), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression.