Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification

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; Ritu Roy; Aaron C Logan; Alexander E Perl; Adam Abate; Adam Olshen; Catherine C Smith

doi:10.1101/2023.05.15.540305

Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification

bioRxiv [Preprint]. 2023 May 18:2023.05.15.540305. doi: 10.1101/2023.05.15.540305.

Authors

Cheryl A C Peretz^{1

2}, Vanessa E Kennedy³, Anushka Walia³, Cyrille L Delley⁴, Andrew Koh³, Elaine Tran³, Iain C Clark⁵, Corey E Hayford⁶, Chris D'Amato⁶, Yi Xue⁶, Kristina M Fontanez⁶, Ritu Roy², Aaron C Logan³, Alexander E Perl⁷, Adam Abate⁴, Adam Olshen^{2

8}, Catherine C Smith^{2

3}

Affiliations

¹ Divison of Hematology and Oncology, Department of Pediatrics, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.
³ Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴ Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
⁵ Bioengineering, University of California Berkeley, Berkeley, CA, USA.
⁶ Fluent Biosciences Inc., Watertown, MA.
⁷ Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Abstract

Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.

Publication types

Preprint

Abstract

Publication types

Grants and funding