Description of a novel subtype of acute myeloid leukemia defined by recurrent <i>CBFB</i> insertions

Ryland, Georgina L.; Umeda, Mikio; Holmfeldt, Linda; Lehmann, Sören; Herlin, Morten; Jing, J; Khanlari, Mahsa; Rubnitz, Jeffrey E.; Ries, Rhonda E.; Kosasih, Hansen J; Ekert, Paul; Goh, Hwee Ngee; Grimmond, Sean M.; Haferlach, Claudia; Day, Ryan B.; Ley, Timothy J.; Meshinchi, Soheil; Ma, Xiaotu; Blombery, Piers; Klco, Jeffery M.

doi:10.1182/blood.2022017874

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…2a,b ). By contrast, mutations in UBTF or CBFB were exclusively found in cases without a defining alteration, as previously shown 8 , 27 , suggesting that these alterations define subgroups with distinct molecular characteristics.…”

Section: Resultssupporting

confidence: 71%

“…Among the remaining cases without class-defining alterations, we found that the following alterations were also mutually exclusive and thus defined them as independent molecular categories: UBTF tandem duplications 8 , GLIS family ( GLIS2-3 ) fusions 7 , fusions of FET and ETS family genes 39 , 40 (for example, FUS :: ERG ), BCL11B SVs 34 (Supplementary Table 12 ), PICALM::MLLT10 , KAT6A rearrangements, MNX1 SVs 41 , RUNX1 fusion with CBFA2T2-3 (ref. 42 ) ( RUNX1::RUNX1T1 -like) and newly reported CBFB insertions ( CBFB -GDXY) 27 (Fig. 2a–c ).…”

Section: Resultssupporting

confidence: 54%

“…In addition to known enrichment of chromosomal events like t(11,x) in pAML, sequencing technologies have identified additional pediatric-enriched driver alterations 7 , 8 , 27 . This prompted us to comprehensively investigate the increasingly complex genomic landscape of pAML in the context of the latest classification systems for hematological malignancies (WHO 5th (ref.…”

Section: Discussionmentioning

confidence: 99%

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A new genomic framework to categorize pediatric acute myeloid leukemia

Umeda,

Ma,

Westover

et al. 2024

Nat Genet

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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.

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Section: Resultssupporting

confidence: 71%

Section: Resultssupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A new genomic framework to categorize pediatric acute myeloid leukemia

Umeda,

Ma,

Westover

et al. 2024

Nat Genet

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show abstract

“…Furthermore, in assays performed in cell lines, CBFB::MYH11 impairs recruitment of RUNX1 protein to a target promoter, rather than recruiting transcriptional repressors ( 45 , 82 ). The transcriptional repressor model for CBFB::MYH11 is also complicated by the recent discovery of a recurrent CBFB D87GDSY insertional mutation in a subset of AMLs that are transcriptionally similar to CBFB::MYH11 AML ( 85 ), without the presence of any domains predicted to interact with transcriptional repressors.…”

Section: Discussionmentioning

confidence: 99%

Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia–initiating CBFB::MYH11 oncofusion protein

Day,

Hickman,

et al. 2023

Journal of Clinical Investigation

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Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis

Umeda

Westover

et al. 2023

Preprint

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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 895 pAML into 23 molecular categories that are mutually distinct from one another, including new 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 prognostic framework for pAML based on molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

show abstract

Description of a novel subtype of acute myeloid leukemia defined by recurrent CBFB insertions

Cited by 3 publications

References 14 publications

A new genomic framework to categorize pediatric acute myeloid leukemia

A new genomic framework to categorize pediatric acute myeloid leukemia

Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia–initiating CBFB::MYH11 oncofusion protein

Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis

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