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

Duployez, Nicolas; Vasseur, Loïc; Kim, Rathana; Largeaud, Laëtitia; Passet, Marie; L'Haridon, Anaïs; Lemaire, Pierre; Fenwarth, Laurène; Geffroy, Sandrine; Hélevaut, Nathalie; Celli-Lebras, Karine; Adès, Lionel; Lebon, Delphine; Berthon, Céline; Marceau-Renaut, Alice; Cheok, Meyling; Lambert, Juliette; Récher, Christian; Raffoux, Emmanuel; Micol, Jean-Baptiste; Pigneux, Arnaud; Gardin, Claude; Delabesse, Éric; Soulier, Jean; Hunault, Mathilde; Dombret, Hervé; Itzykson, Raphaël; Clappier, Emmanuelle; Preudhomme, Claude

doi:10.1038/s41375-023-01906-z

Cited by 11 publications

(21 citation statements)

References 43 publications

(52 reference statements)

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“…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.…”

Section: Discussionsupporting

confidence: 88%

“…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).…”

Section: Discussionsupporting

confidence: 76%

“…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.…”

Section: Clinical Features Of Ubtf-td Pediatric Myeloid Neoplasmssupporting

confidence: 71%

“…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.…”

Section: Introductionmentioning

confidence: 95%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Barajas,

Umeda,

Contreras

et al. 2023

Preprint

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Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features ofUBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 ofUBTF. We demonstrate thatUBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm thatUBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition ofFLT3orWT1mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 ofUBTFthat phenocopy exon 13 duplications, expanding the spectrum ofUBTFalterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS withUBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.Key PointsLargest cohort of pediatricUBTF-TD in myeloid neoplasms reported to date.Use of single-cell DNA+protein sequencing technology in 3UBTF-TD samples reveals a clonal evaluation pattern characterized by sequential acquisition ofWT1andFLT3mutations and a more stem cell-like protein expression pattern.Pediatric MDS and AML patients withUBTF-TD alterations dysplastic features with an increase erythroid precursors.Tandem duplications in exon 9 ofUBTFrepresent a rare but functionally equivalent subgroup ofUBTF-TD myeloid neoplasms.Impact StatementUBTFtandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatricUBTF-TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 76%

Section: Clinical Features Of Ubtf-td Pediatric Myeloid Neoplasmssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Barajas,

Umeda,

Contreras

et al. 2023

Preprint

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Persistence of UBTF tandem duplications in remission in acute myeloid leukaemia

Harrop,

Nguyen,

Byrne

et al. 2023

eJHaem

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UBTF tandem duplications are recurrent in adult and paediatric acute myeloid leukaemia and have been reported to be associated with a poor prognosis. Co‐mutations in WT1 and FLT3 are common while morphological dysplasia is frequent. The role of UBTF‐TDs in leukemogenesis is yet to be elucidated; however they have been proposed as early initiating events, making them attractive for assessment of MRD and a potential therapeutic target. We present two cases where the UBTF‐TD was observed in remission and discuss the implications of these findings in the clinicobiological understanding of this emerging entity.

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Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

Cuglievan,

Kantarjian,

Rubnitz

et al. 2024

Leukemia

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Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

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

Cited by 11 publications

References 43 publications

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

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

Persistence of UBTF tandem duplications in remission in acute myeloid leukaemia

Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

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