UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia

Abstract

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis

“…In this pediatric cohort, we observed that UBTF- TD is associated with an M2 morphology subtype (44.2%) according to FAB classification (27). These morphological features align with findings in adult cases, which showed a high prevalence of FAB M6 and M2 cases (9). Furthermore, the presence of dysplastic features and the observation that UBTF -TD occurs in cases of pediatric MDS suggest that MDS and AML could be part of a continuum driven by UBTF -TD.…”

“…In this study, we extended our cohort of pediatric myeloid malignancies with exon 13 UBTF -TD, which now includes 95 pediatric cases. Similar to studies in adults (9), pediatric myeloid tumors with UBTF- TD are associated with lower bone marrow blast infiltration and lower white blood cell count, suggesting a similar clinical presentation. In this pediatric cohort, we observed that UBTF- TD is associated with an M2 morphology subtype (44.2%) according to FAB classification (27).…”

“…UBTF-TD AML showed a variety of morphologic features associated with cellular differentiation, as evidenced by variable FAB (French-American-British) classifications (Figure 3A, Supplemental Table 4). Although AML with maturation (FAB M2) was the most common (19/43, 44.2%), cases with FAB M6 (erythroid) features were also observed, as was also recently described for UBTF-TD AMLs in adults (9). Morphologic assessments also revealed that UBTF-TD cases often displayed pleomorphic blasts (Figure 3B), accompanied by background multilineage dysplasia and increased erythroid precursors.…”

“…Recurrent tandem duplications (TD) of exon 13 of upstream binding transcription factor ( UBTF ) were only recently identified as potential initiating events in pediatric AML (4–7), accounting for about 4% of newly diagnosed pediatric AML. PCR-based screening covering exon 13 of UBTF also identified UBTF -TD alterations in large adult AML cohorts (8, 9). These studies significantly contributed to the accumulation of evidence of UBTF- TD alterations in adult AML.…”

“…These studies significantly contributed to the accumulation of evidence of UBTF- TD alterations in adult AML. However, PCR-based methods potentially underestimate partial tandem duplications (PTD) extending outside the regions covered by amplicons or possible alterations not involving exon 13 (9). Also, data on UBTF alterations in pediatric AML is limited to screening of relatively small cohorts (4, 5), and further efforts are needed to accumulate more knowledge about the biology and clinicopathologic features of this disease entity.…”