UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome

Abstract

Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.

Acute myeloid leukemias with UBTF tandem duplications are sensitive to menin inhibitors

“… 4 , 5 , 11 , 12 Recent studies have now shown that UBTF -TDs are not restricted to pediatric AML but also occur in ∼ 3% of adult AML patients aged 18 to 60 years (median age = 37 years). 9 , 10 UBTF alterations have also recently been described in B-cell acute lymphoblastic leukemia, although these are structural variations leading to focal deletions of exons 18 to 21, resulting in UBTF::ATXN7L3 fusions. 6 , 7 , 8 The recent identification of novel UBTF alterations in hematological malignancies highlights a critical need to understand how UBTF alterations drive leukemogenesis.…”

“…Recently, UBTF has gained increased interest in hematological malignancies, such as acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Recurrent exon 13 tandem duplications (TD) in UBTF have emerged as a major subtype-defining genomic alteration in pediatric AML that is associated with poor prognosis 4 , 5 , 11 , 12 and has also recently been reported in ∼3% of adults aged 18 to 60 years 9 and 1.2% of all individuals over 18 years of age. 10 UBTF -TDs have a high variant allele frequency and are preserved during disease progression.…”

“… 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Recurrent exon 13 tandem duplications (TD) in UBTF have emerged as a major subtype-defining genomic alteration in pediatric AML that is associated with poor prognosis 4 , 5 , 11 , 12 and has also recently been reported in ∼3% of adults aged 18 to 60 years 9 and 1.2% of all individuals over 18 years of age. 10 UBTF -TDs have a high variant allele frequency and are preserved during disease progression. Patients with UBTF -TD AML are associated with high measurable residual disease positivity and poor outcomes, suggesting an overall poor response to conventional chemotherapy.…”

Genomics has more to reveal

“…It is estimated that UBTF -TD affect 4% of pediatric AML cases (9% of relapsed pediatric AML cases) [ 9 ], 3% of young adult AML cases (ages 18–60 y), and less than 0.5% of cases after age 60 y [ 10 , 11 ]. These studies have also demonstrated a close continuum with MDS.…”

“…These studies have also demonstrated a close continuum with MDS. In a recent series of adult AML, 20% of cases with UBTF -TD were secondary to an MDS [ 11 ]. The study of pediatric MDS cases without genetic predisposition found a frequency of about 30% for UBTF -TD mutations [ 12 ].…”