RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features

Abstract

We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1/ASXL1 (OS, P=0.004), RUNX1/SRSF2 (OS, P=0.007) and RUNX1/PHF6 (OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1/IDH2 (OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.

Genetic regulation of the RUNX transcription factor family has antitumor effects

“…By further exploring our prior finding that RUNX is a prerequisite for the initiation of leukemia development (10,11), we now reveal that RUNX plays a pivotal role in the maintenance of leukemia cells as well as tumor cells derived from different origins. According to a previous report, the frequency of RUNX1 point mutations in the Runt domain among de novo adult AML cases is around 10% (41). Some of these mutant RUNX1 (such as D171N and S291fsX300 mutations) and RUNX1 fusion genes (such as RUNX1-ETO and RUNX1-ETO9a) are proven oncogenes in mice with a p53-proficient environment (42).…”

<b><i>RUNX1</i></b> Mutations Can Lead to Aberrant Expression of CD79a and PAX5 in Acute Myelogenous Leukemias: A Potential Diagnostic Pitfall

“…In FPD/AML, > 40 different RUNX1 mutations are described and show varied distribution at many different sites [13], but they are expected to occur with a VAF near to 50 or 100%. Additional prototypic mutations of AML such as DNMT3A , NRAS , and SRSF2 in 2 patients, and PTPN11 and TET2 in 1 patient each, respectively, were detected (Table 1); these mutations as well as the tetrasomy 13 of cases 1 and 4 being prototypic for RUNX1 -mutated AML subcohorts of larger studies [14]. All cases were devoid of t(8: 21).…”

Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions

“…15,16 Although RUNX1 has been shown to exhibit both oncogenic and oncosuppressive properties context-dependently in various cancers, little has been known about the molecular mechanisms underlying this curious bidirectional function of RUNX1. 3,5,15,17,18 In addition, although mutations in RUNX1 have been reported to demarcate poorer-prognostic cohorts in AML patients, [19][20][21] the level of RUNX1 expression itself has not been directly linked to the outcomes of AML patients. Recently, we have reported that RUNX cluster regulation is a promising therapeutic strategy against various types of cancers, including AML.…”