Abstract
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.
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Data availability
The next generation sequencing data for the current study are available from the corresponding author on reasonable request through St. Jude Cloud (https://www.stjude.cloud/).
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Acknowledgements
We thank all the patients and their families at St. Jude Children’s Research Hospital (SJCRH) and collaborating centers for their contribution of the biological specimens used in this study. We thank Dr. Yiping Fan for expert advice on gene expression analysis of RNA-seq data. Elizabeth Caldwell was supported by R25CA23944 from the National Cancer Institute. The work was partially supported by ALSAC.
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LW, JER, and JMK conceived and designed the study. JM, YCL, RKV, and LW extracted and analyzed data, and interpreted results. JM, JM, WR, MC, SF, and MRW were responsible for bioinformatics. JER, HI, RKV, JMK, and LW extracted and analyzed clinical data. AP and EC organized data, contributed to writing the manuscript, and updated reference lists. MU contributed to data extraction and provided feedback on the manuscript.
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Ma, J., Liu, YC., Voss, R.K. et al. Genomic and global gene expression profiling in pediatric and young adult acute leukemia with PICALM::MLLT10 Fusion. Leukemia (2024). https://doi.org/10.1038/s41375-024-02194-x
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DOI: https://doi.org/10.1038/s41375-024-02194-x