Immunophenotypic, Genetic, and Clinical Features Associated With RUNX1 Mutation in Acute Leukemias and Chronic...

RUNX1 is a commonly mutated transcriptional regulator of hematopoiesis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mutated RUNX1 (mRUNX1) may associate with cross-lineage immunophenotypic aberrancy, presenting potential complications for blast lineage assignment at diagnosis.

Clinical and laboratory data were reviewed for patients with RUNX1 mutations (N = 125) at Vancouver General Hospital from 2016 to 2022. Diagnostic flow cytometry data were reanalyzed, and RUNX1 mutation characteristics and associations with pathologic, comutation, and flow cytometric features were assessed.

Missense RUNX1 mutations (overall 42.9% missense, 57.1% truncating) were enriched in the runt homology domain (RHD; 81.7%, Adj. p = 0.011). Several recurrent hotspot mutations were seen, including common hotspot variants. The most commonly comutated genes with RUNX1 in both acute leukemia with mRUNX1 and MDS-mRUNX1 were ASXL1 (44.4%; 59.3%), SRSF2 (40.7%; 37.3%), and TET2 (35.8%; 55.9%). The mRUNX1 group demonstrated frequent positivity for B-lymphoid markers, with 14.4% having increased expression in at least three B-lineage markers. Differences in antigen expression were associated with RUNX1 mutation type and location, with increased CD10 expression associated with RUNX1 mutations in the RHD (Adj. p = 0.02764), and increased CD79a expression associated with RUNX1 missense mutations (Adj. p = 0.004452).

In our cohort, we observed missense variants clustering in the RHD and recurrence of common pathogenic variants. Higher-risk comutations were found in a substantial fraction of mRUNX1 cases which may contribute to its adverse risk associations. Comparable degrees of aberrancy in B-lineage markers were seen in mRUNX1 patients versus the comparator cohorts of MPAL-wtRUNX1 and AML with rearranged RUNX1.