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.

Fig. 1. UBTF-TDs in adult AML.

A Fragment analysis of mutant (665 bp) and wild-type (617 bp) alleles of UBTF in a patient with a 48-bp tandem duplication. B Integrative Genomics Viewer (IGV) visualization showing the soft-clipped reads and increased coverage in UBTF exon 13. C UBTF gene structure and location of UBTF-TDs. The common minimal duplicated motif in exon 13 is highlighted in red.

Fig. 2. Baseline biological features associated with UBTF-TDs.

A Mutational landscape of AML with UBTF-TD. Only genes with at least one mutation in one patient are shown. The full list of screened genes is given in the Supplementary Table 2. B BM blast infiltration and (C) WBC count according to UBTF and NPM1 status in AML patients aged 18–60 years. The black bars indicate the median values. (D) Associations among gene and cytogenetic abnormalities in AML patients aged 18–60 years. (E) BM blast infiltration, (F) WBC count and (G) BM morphology classification according to FLT3-ITD status in UBTF-TD AML. The FiLT3r algorithm was used for detection and precise quantification of FTL3-ITDs [23]. H BM morphology in patient #L171D0708G (FLT3-ITD with VAF < 5%) and (I) patient #L151D4757X (FLT3-ITD negative) showing characteristic dyserythropoiesis and blasts with rare Auer rods (red arrow). J BM morphology in patient #L221T6545N (FLT3-ITD with VAF > 70%) showing massive blast infiltration.

Fig. 3. Swimmer plot graph of adult AML patients with UBTF-TDs.

Each bar represents one patient in the study. Only patients with available follow-up (n = 35) are shown.

Fig. 4. Clinical outcome of UBTF-TD AML 18–60 y.

A Disease-free survival in patients achieving CR or CRp after induction and (B) overall survival according to UBTF status and ELN 2022 risk stratification. Study restricted to patients enrolled in the ALFA-0702 trial with available ELN 2022 risk stratification.

Fig. 5. Patterns of clonal evolution in UBTF-TD AML.

Fishplots are imputed from VAFs obtained by bulk NGS at AML diagnosis and during disease progression (relapsed or refractory AML). Twelve patients with available matched samples are presented: (A–J) Relapsed AML; (K–L) Refractory AML. Disappearance of all mutations (including UBTF-TD) in CR was verified by NGS (1% threshold) in patients A, B, C, and G and was assumed in the others. Details about patient history are provided in the Fig. 3. Figure made with the Fishplot package for R (version 4.2.0) [26].