Measurable Residual Disease in UBTF‐TD Adult Acute Myeloid Leukemia

Tandem duplications in the Upstream Binding Transcription Factor (UBTF-TD) gene have been recently described as a recurrent lesion in acute myeloid leukemia (AML), associated with younger age, morphological dysplasia, WT1 mutations, and poor prognosis [1-4]. This study aimed to characterize UBTF-TDs in our adult AML cohort and explore the clinical utility of WT1 expression as a marker of measurable residual disease (MRD) in this subgroup of AML [5]. Molecular analysis of UBTF-TD was performed on DNA from bone marrow or infiltrated peripheral blood. Exon 13 was analyzed by capillary electrophoresis and confirmed by Sanger sequencing if mutated. The copy number of mRNA WT1 at diagnosis was studied by qPCR. WT1 and UBTF expression were assessed at different times to follow MRD in 7 and 5 patients, respectively. To calculate the incidence of UBTF-TD in adult AML, we studied consecutively all patients included in the CETLAM AML-12 protocol between 2012 and 2017 (n = 410) and identified 7 (1.7%) cases with UBTF-TD. When patients below 30 years of age were selected (n = 34), their incidence reached 11.8%. From 2018 onwards, given the availability of NGS data and the strong association of UBTF-TD with WT1 mutations, we studied directly patients with WT1-mutated AML (n = 53) and detected other 7 (13.2%) UBTF-TDs. In our cohort, UBTF-TD was associated with a younger age at onset compared to UBTFWT patients (median 38 vs. 55 years, p < 0.001). All of them presented myelodysplastic changes in the bone marrow aspirate. Regarding genomics, UBTF-TD patients presented a unique molecular profile with a strong association with trisomy 8 (28.6% vs. 12.8%; p = 0.045), FLT3-ITD (42.9% vs. 20.7%; p = 0.046) and WT1 mutations (66.7% vs. 8.9%; p < 0.001). Additionally, the presence of UBTF-TD was mutually exclusive with other class-defining lesions such as NPM1 mutations (p = 0.009). Among the 14 UBTF-TD patients, the copy number of WT1/ABL x 104 at diagnosis was considerably high (mean = 10 064; range 1319–59 705). Regarding the monitoring of WT1 levels throughout disease progression, two relapsed patients exhibited a modest increase in WT1 levels before relapse, followed by a pronounced rise at the time of relapse (Figure 1, Cases 6 and 7). In contrast, the remaining 5 cases who did not experience relapse showed no significant changes in WT1 levels. Case 3 is a representative example (Figure 1). Likewise, UBTF expression displays a similar behavior during follow-up (Figure 2). Although UBTF-TD was barely detectable in Case 6 before relapse, it became present during relapse. In Case 7, a clear correlation between UBTF-TD expression and disease progression was observed. Our findings confirm that AML with UBTF-TD possesses distinctive clinical and biological features. Although it is a rare finding in adult cohorts, its likelihood is much higher in younger patients without other class-defining lesions. We also evaluate through UBTF expression how the UBTF-TD mutation reflects disease progression. Further, we demonstrate that the quantification of WT1 mRNA, alone or in combination with UBTF expression or other techniques, could be an excellent marker for studying MRD in UBTF-TD AML and has some advantages compared to DNA-based methods [6]. H.C. and J.N. conceived and designed the study. H.C., G.R., and M.C. performed laboratory analysis and assembled the data. G.O., A.A., M.P., O.S., A.C., S.V., M.T., M.M., D.G., J.M.T., A.G., J.S., J.E., and J.N. provided clinical data. This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all study participants. The authors declare no conflicts of interest.