SETBP1 mutation

Notably, SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes an iPSC-based model of GATA2 deficiency, offering new insights into myeloid disease progression and a platform for testing future therapeutic strategies.

Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

AML progression frequency for non-AML cases did not significantly differ between the 3 groups. Survival of SETBP1m/GATA2m patients was not worse compared to SETBP1wt/GATA2m or SETBP1m/GATA2wt.

Improved survival was observed with transplantation in groups DP2, DP7, and DP9. These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

On multivariate analysis, age ≥ 70 years (p = 0.004) and higher peripheral blood blasts (p = 0.02) had worse OS. Patients with Ile871m had lower OS when compared with Asp868m and Gly870m (5.5 months vs. 17.4 and 17 months, respectively, p = 0.1).

According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Compared to a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P <.001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Clinically, a striking difference in disease aggressiveness was noted, with SETBP1-mutated patients showing a much worse clinical course. As opposite to myelodysplastic/myeloproliferative neoplasms, where SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in three TN-PMF patients 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.

STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.