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

Umeda, Mikio; Ma, Jing; Westover, Tamara; Ni, Yonghui; Song, Guangchun; Maciaszek, Jamie L.; Rusch, Michael; Rahbarinia, Delaram; Foy, Scott G.; Huang, Benjamin; Walsh, Michael P.; Kumar, Priyadarshini; Liu, Yanling; Fan, Yiping; Wu, Gang; Baker, Sharyn D.; Ma, Xiaotu; Wang, Lu; Rubnitz, Jeffrey E.; Pounds, Stanley; Klco, Jeffery M.

doi:10.21203/rs.3.rs-2925426/v1

Cited by 2 publications

(1 citation statement)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the relatively common recurrence of PICALM::MLLT10 fusion in T-ALL/LLy (PM-T-ALL/LLy), its immunophenotypic correlation and prognostic impact in this subgroup of leukemia has been widely studied [8]; in contrast, data regarding PICALM::MLLT10-positive AML (PM-AML) are scarce due to its rarity as it occurs in less than 1% of pediatric AML cases [9]. Moreover, previous case series studies have focused on clinical and immunophenotypic features, whereas comprehensive molecular profiling of PICALM::MLLT10-positive acute leukemias has not yet been addressed.…”

Section: Introductionmentioning

confidence: 99%

Genomic and Global Gene Expression Profiling in Pediatric and Young Adult Acute Leukemia with PICALM::MLLT10 Fusion

Wang,

Ma,

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

PICALM::MLLT10 fusion is a rare but recurrent genetic driver in acute leukemias. To better understand the genomic landscape of PICALM::MLLT10 (PM) positive acute leukemia, we performed genomic profiling and gene expression profiling in twenty PM-positive patients, including AML (n = 10), T-ALL/LLy (n = 8), Mixed-phenotype acute leukemia (MPAL), T/B (n=1) and acute undifferentiated leukemia (AUL) (n=1). Besides confirming the known activation of HOXA, our study suggested PHF6 disruption as a key cooperating event in PICALM::MLLT10-positive leukemias. In addition, we demonstrated differences in gene expression profiles as well as remarkably different spectra of co-occurring mutations between PM-AML and PM-ALL (including T-ALL/LLy and MPAL, T/B). Alterations affecting TP53 and NF1 are hallmarks of PM-AML and are strongly associated with disease progression and relapse, whereas EZH2 alterations are highly enriched in PM-ALL. This comprehensive genomic and transcriptomic profiling provides insights into the pathogenesis and development of PICALM::MLLT10 positive acute leukemia. The dramatic differences in the landscapes of co-occurring mutations for these related acute leukemia subtypes highlight the value of performing real-time genomic profiling of acute leukemia for molecular diagnostics.

show abstract

Section: Introductionmentioning

confidence: 99%

Genomic and Global Gene Expression Profiling in Pediatric and Young Adult Acute Leukemia with PICALM::MLLT10 Fusion

Wang,

Ma,

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

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

Barajas,

Umeda,

Contreras

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 2 publications

References 141 publications

Genomic and Global Gene Expression Profiling in Pediatric and Young Adult Acute Leukemia with PICALM::MLLT10 Fusion

Genomic and Global Gene Expression Profiling in Pediatric and Young Adult Acute Leukemia with PICALM::MLLT10 Fusion

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

Contact Info

Product

Resources

About