Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia

Cheryl A. C. Peretz, Vanessa E. Kennedy, Anushka Walia, Cyrille L. Delley, Andrew Koh, Elaine Tran, Iain C. Clark, Corey E. Hayford, Chris D’Amato, Yi Xue, Kristina M. Fontanez, Aaron A. May-Zhang, Trinity Smithers, Yigal Agam, Qian Wang, Hai-ping Dai, Ritu Roy, Aaron C. Logan, Alexander E. Perl, Adam Abate, Adam Olshen and Catherine C. Smith ()
Additional contact information
Cheryl A. C. Peretz: University of California San Francisco
Vanessa E. Kennedy: University of California San Francisco
Anushka Walia: University of California San Francisco
Cyrille L. Delley: University of California San Francisco
Andrew Koh: University of California San Francisco
Elaine Tran: University of California San Francisco
Iain C. Clark: University of California Berkeley
Corey E. Hayford: Fluent Biosciences Inc.
Chris D’Amato: Fluent Biosciences Inc.
Yi Xue: Fluent Biosciences Inc.
Kristina M. Fontanez: Fluent Biosciences Inc.
Aaron A. May-Zhang: Fluent Biosciences Inc.
Trinity Smithers: Fluent Biosciences Inc.
Yigal Agam: Fluent Biosciences Inc.
Qian Wang: The First Affiliated Hospital of Soochow University
Hai-ping Dai: The First Affiliated Hospital of Soochow University
Ritu Roy: University of California San Francisco
Aaron C. Logan: University of California San Francisco
Alexander E. Perl: Perelman School of Medicine at the University of Pennsylvania
Adam Abate: University of California San Francisco
Adam Olshen: University of California San Francisco
Catherine C. Smith: University of California San Francisco

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

Date: 2024
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DOI: 10.1038/s41467-024-52317-2

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