RUNX1 mutations contribute to the progression of MDS due to disruption of antitumor cellular defense: a study on patients with lower-risk MDS

Abstract

Patients with lower-risk myelodysplastic syndromes (LR-MDS) have a generally favorable prognosis; however, a small proportion of cases progress rapidly. This study aimed to define molecular biomarkers predictive of LR-MDS progression and to uncover cellular pathways contributing to malignant transformation. The mutational landscape was analyzed in 214 LR-MDS patients, and at least one mutation was detected in 137 patients (64%). Mutated RUNX1 was identified as the main molecular predictor of rapid progression by statistics and machine learning. To study the effect of mutated RUNX1 on pathway regulation, the expression profiles of CD34 + cells from LR-MDS patients with RUNX1 mutations were compared to those from patients without RUNX1 mutations. The data suggest that RUNX1-unmutated LR-MDS cells are protected by DNA damage response (DDR) mechanisms and cellular senescence as an antitumor cellular barrier, while RUNX1 mutations may be one of the triggers of malignant transformation. Dysregulated DDR and cellular senescence were also observed at the functional level by detecting γH2AX expression and β-galactosidase activity. Notably, the expression profiles of RUNX1-mutated LR-MDS resembled those of higher-risk MDS at diagnosis. This study demonstrates that incorporating molecular data improves LR-MDS risk stratification and that mutated RUNX1 is associated with a suppressed defense against LR-MDS progression.

MDS subclassification—do we still have to count blasts?

“…In our study mutations in RUNX1 and ASXL1 defined distinct subgroups within spliceosome mutated MDS potentially driving progression. This is concordant with previous reports demonstrating that RUNX1 and ASXL1 mutations contribute to the progression in lower-risk MDS, are more frequently mutated in rapidly progressing patients [11] and correlate with unfavorable outcome in MDS [12,13]. We previously reported that RUNX1 mutations are independent negative prognostic factors for OS and AML transformation in SF3B1 mut MDS [14].…”

CCAS: One-stop and comprehensive annotation system for individual cancer genome at multi-omics level

“…Abnormalities occur at SNV/Indels levels (Abnormalities in user’s upload data section). Moreover, ARID1A is involved in 2 pathways including the RUNX1 pathway, which plays an important role in the development of leukemia (Pathways section) ( Kaisrlikova et al, 2022 ). The literature section indicates that ARID1A is observed in a variety of cancers including bladder cancer ( Saito et al, 2018 ; Cao et al, 2020 ), ovarian cancer ( Kim et al, 2016 ), liver cancer ( Sun et al, 2017 ) and colon cancer ( Mathur et al, 2017 ; Iftekhar et al, 2021 ).…”

Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study

“…36,37 Although these mutations have not been included in the guidelines as progression factors, some of them assuredly predict poor outcomes and even result in the development of acute myeloid leukemia. 38,39 On the other hand, previous studies of HMA (decitabine)treated patients with MDS-EB showed that genetic relapse can predate morphological relapse. 40,41 This indicates that gene examination after treatment is also vitally important to monitor tumor burden.…”