Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia
Cheryl A C Peretz1,2, Vanessa E Kennedy3, Anushka Walia3
1Division of Hematology and Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
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.
Insights
Mixed phenotype acute leukemia (MPAL) blasts share a stem cell-like profile, indicating high differentiation potential. This potential predicts poorer survival and offers a new strategy for risk stratification in MPAL patients.
Area of Science:
- Hematology
- Oncology
- Genomics
Background:
- Mixed phenotype acute leukemia (MPAL) lacks defined driver mutations and predictive subtypes.
- Current therapeutic strategies for MPAL are unclear, with a generally poor prognosis.
Purpose of the Study:
- To characterize the transcriptional, immunophenotypic, and genetic landscapes of MPAL using multiomic single-cell profiling.
- To identify potential biomarkers for risk stratification in MPAL.
Main Methods:
- Multiomic single-cell profiling of 14 newly diagnosed adult MPAL patients.
- Analysis of transcriptional, immunophenotypic, and genetic data.
- Development and validation of a gene set score (MPAL95) using bulk RNA sequencing.
Main Results:
- MPAL blasts exhibit a shared stem cell-like transcriptional profile, suggesting high differentiation potential.
- Genetic profiles and transcriptomes do not reliably correlate with MPAL immunophenotypes.
- Higher differentiation potential correlated with inferior survival in the studied cohort.
Conclusions:
- A stem cell-like transcriptional profile in MPAL is linked to high differentiation potential and poor prognosis.
- The MPAL95 gene set score, derived from stem-like MPAL cells, predicts survival in an independent cohort.
- MPAL95 offers a potential strategy for clinical risk stratification in MPAL.
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