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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229666 | GEO | 2024/02/12

REPOSITORIES: GEO

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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [RNA-seq]

Project description:UBTF tandem duplications (TD) have recently emerged as a subtype-defining alteration in pediatric acute myeloid leukemia (pAML), which is characterized by HOXB gene dysregulation and a poor response to conventional chemotherapy. Here, we use protein-protein interaction studies to show that UBTF-TD maintains interactions with components of the RNA pol I complex, while also engaging with a network of unique protein interactors specific to UBTF-TD, like KMT2A. These data suggest that UBTF- TD both preserves canonical UBTF functions and demonstrates gain of function activities. Furthermore, we show that UBTF-TD and KMT2A co-localize to key genomic targets dysregulated in UBTF-TD myeloid malignancies, like HOXB gene clusters and MEIS1. Using a protein degradation system, we show that stemness, proliferation, and the HOXB molecular signature are dependent on sustained UBTF-TD localization to chromatin. Finally, we show UBTF-TD leukemias are sensitive to menin inhibition—providing a viable therapeutic strategy for children with this high-risk AML subtype.

2024-02-12 | GSE229663 | GEO

UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

2024-02-12 | GSE229664 | GEO

UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

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UBTF tandem duplication AMLs are sensitive to menin inhibition

Project description:To investigate the effect of Menin inhibitor on UBTF-TD harboring AML. We characterized UBTF-TD interaction with KMT2A and Menin in different leukemia models including KMT2A-r, transduced and normal cbCD34+ cells as well as in primary AML cells with UBTF-TD mutation. We also analized gene expression pattern upon treatment with Menin inhibitor.

2023-12-01 | GSE233810 | GEO

UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [RNA-seq]

Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [RNA-seq]

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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

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UBTF tandem duplication AMLs are sensitive to menin inhibition

Project description:UBTF tandem duplication AMLs are sensitive to menin inhibition

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UBTF tandem duplication defines High-risk Pediatric Acute Myeloid Leukemia

Project description:Genomic profiling of relapsed pediatric AML demonstrated an increase in KMT2A and NUP98 rearrangements when compared to de novo pediatric AML, as well as an increase in WT1 mutations. Notably, we identified recurrent (9% of relapse cohort) exon 13 duplications in UBTF in pediatric AML cases that previously lacked known driver alterations. These UBTF-tandem duplication (TD) pediatric AMLs occur in approximately 4% of all pediatric AMLs and are less common in adult AMLs, are associated with normal karyotype or trisomy 8 cytogenetic abnormalities, co-occur with WT1 and FLT3-ITD, have an expression profile similar to NUP98-NSD1 and NPM1 mutant AMLs and are independently associated with poor outcome.

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Persistence of <i>UBTF</i> tandem duplications in remission in acute myeloid leukaemia.

Project description: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.

| S-EPMC10660390 | biostudies-literature

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

Project description: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.

| S-EPMC10244165 | biostudies-literature

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