First-hit SETBP1 mutations cause a myeloproliferative disorder with bone marrow fibrosis

• Published in: Blood 2024-04, Vol.143 (14), p.1399-1413
• Main Authors: Crespiatico, Ilaria, Zaghi, Mattia, Mastini, Cristina, D’Aliberti, Deborah, Mauri, Mario, Mercado, Carl Mirko, Fontana, Diletta, Spinelli, Silvia, Crippa, Valentina, Inzoli, Elena, Manghisi, Beatrice, Civettini, Ivan, Ramazzotti, Daniele, Sangiorgio, Valentina, Gengotti, Michele, Brambilla, Virginia, Aroldi, Andrea, Banfi, Federica, Barone, Cristiana, Orsenigo, Roberto, Riera, Ludovica, Riminucci, Mara, Corsi, Alessandro, Breccia, Massimo, Morotti, Alessandro, Cilloni, Daniela, Roccaro, Aldo, Sacco, Antonio, Stagno, Fabio, Serafini, Marta, Mottadelli, Federica, Cazzaniga, Giovanni, Pagni, Fabio, Chiarle, Roberto, Azzoni, Emanuele, Sessa, Alessandro, Gambacorti-Passerini, Carlo, Elli, Elena Maria, Mologni, Luca, Piazza, Rocco
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - genetics; Hematopoietic System; Humans; Mice; Mutation; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders - genetics; Nuclear Proteins - genetics; Primary Myelofibrosis - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023021349

•SETBP1 mutations, acting as a first-hit/early event, drive an aggressive myelofibrosis-like myeloproliferative disorder.•SETBP1 mutations discriminate between 2 subtypes of triple-negative myelofibrosis, with different genetic landscape and aggressiveness. [Display omitted] SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants. SETBP1 is a transcription factor that is mutated in various myeloid neoplasms. Crespiatico and colleagues used a murine model and patient samples to show that SETBP1 mutations act as an early event to drive an aggressive myelofibrosis occurring in the absence of JAK2, MPL, or CALR mutations (so-called triple-negative myelofibrosis). The study provides novel insights into how early mutations can highjack hematopoiesis to drive disease phenotype while at the same time providing a biomarker for some cases of triple-negative myelofibrosis.