Genomic and global gene expression profiling in pediatric and young adult acute leukemia with PICALM::MLLT10 Fusion

• Published in: Leukemia 2024-05, Vol.38 (5), p.981-990
• Main Authors: Ma, Jingqun, Liu, Yen-Chun, Voss, Rebecca K., Ma, Jing, Palagani, Ajay, Caldwell, Elizabeth, Rosikiewicz, Wojciech, Cardenas, Maria, Foy, Scott, Umeda, Masayuki, Wilkinson, Mark R., Inaba, Hiroto, Klco, Jeffery M., Rubnitz, Jeffrey E., Wang, Lu
• Format: Article
• Language: English
• Subjects: 38; 38/91; 45; 45/23; 631/208/69; 631/67/1990/283; Acute lymphoblastic leukemia; Acute myeloid leukemia; Adolescent; Adult; Biomarkers, Tumor - genetics; Cancer Research; Cell proliferation; Child; Child, Preschool; Critical Care Medicine; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genomics; Genomics - methods; Hematology; Hematopoietic stem cells; Humans; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Lymphocytes T; Male; Medicine; Medicine & Public Health; Oncogene Proteins, Fusion - genetics; Oncology; p53 Protein; Pathogenesis; Pediatrics; Phenotypes; Prognosis; Stem cells; Transcription Factors - genetics; Transcriptome; Transcriptomics; Young Adult; Young adults
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-024-02194-x

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, differential gene expression analysis compared to hematopoietic stem cells demonstrated the enrichment of genes associated with cell proliferation-related pathways and relatively high expression of XPO1 in PM-AML and PM-T-ALL/LLy. Our study also 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-T-ALL/LLy. Alterations affecting TP53 and NF1, hallmarks of PM-AML, are strongly associated with disease progression and relapse, whereas EZH2 alterations are highly enriched in PM-T-ALL/LLy. This comprehensive genomic and transcriptomic profiling provides insights into the pathogenesis and development of PICALM::MLLT10 positive acute leukemia.