A new genomic framework to categorize pediatric acute myeloid leukemia

Abstract

Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

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

“…In particular, UBTF tandem duplications have been characterized as subtype-defining genomic alterations in childhood AML associated with HOX gene dysregulation. 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.…”

“…At the transcriptional level, UBTF -TD AMLs are similar to other well-defined AML subtypes, including NUP98- rearranged ( NUP98- r, ie, NUP98::NSD1 ), NPM1 mutations, DEK::NUP214 , KMT2A- rearranged ( KMT2A -r), and KMT2A partial tandem duplication ( KMT2A- PTD) AMLs. 4 , 12 The similarities in the transcriptional profiles of these AML subtypes suggest a shared mechanism. Similar to AMLs with NPM1 mutations or KMT2A fusion oncoproteins, 16 we demonstrate that UBTF-TD, KMT2A, and menin co-occupy genomic regions that are transcriptionally dysregulated in UBTF -TD leukemias ( Figures 1 and 2 ).…”

“…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.…”

<i>UBTF</i> tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: implications for clinical screening and diagnosis

“…Pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are characterized by unique genetic backgrounds when compared to those in adults. 1-3 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.…”

Activity of the MEK inhibitor trametinib in a patient with a BRAF mutation persisting from T‐lymphoblastic lymphoma through lineage switch to CNS acute myeloid leukemia

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BRAF mutations occur in approximately 1% of pediatric and adult acute myeloid leukemia (AML) 1,2 and less than 2.5% of acute lymphoblastic leukemia/lymphoma cases. [3][4][5][6] While BRAF mutations are rare in acute leukemias, multiple studies have demonstrated overactivity of the RAS/MAPK signaling pathway.

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