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Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification [DAb-seq]

ABSTRACT: Mixed phenotype acute leukemia (MPAL) also known as acute leukemia of ambiguous lineage (ALAL), is characterized by leukemic blasts with both lymphoid and myeloid cell surface markers. Here, we use SC multiomic profiling on newly diagnosed MPAL samples to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. This profiling allows us to definitively contradict the paradigm of MPAL as a disease on a continuum with myeloid and lymphoid lineage acute leukemias, and instead identifies MPAL as a distinct, stem-like disease that, unlike other leukemias, cannot be defined by genetics alone. We further describe a stem cell gene expression signature for MPAL that can predict patient survival. These results broaden our understanding of MPAL biology and suggest a path toward novel risk stratification for MPAL. Importantly, these findings have potential to direct treatment and, hopefully, ultimately improve the prognosis of this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230827 | GEO | 2023/08/07

REPOSITORIES: GEO

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Project description:We aim to compare the genomic discrepancies across de novo Ph+ ALL, Ph+ MPAL and Ph+ AML, three diseases characterized by the occurrence of BCR-ABL1 transcripts but showing varied immunophenotypes. The data we are now submitting is the genomic copy number variants of these three groups. The following is the abstract with associated manuscript. The chromosome abnormality of Philadelphia (Ph) is typically seen in de novo acute lymphoblastic leukemia (ALL). It has also been identified in mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) in the revisions to World Health Organization classification of myeloid neoplasms and actue leukemia. The discrepancies between these patients and potential mechanisms underlying differentiation fate of the leukemia cells remain poorly defined. We evaluated the clinical, genomic and transcriptomic features of Ph+ ALL, Ph+ MPAL and Ph+ AML by taking advantage of high-density genomic analysis, including next-generation sequencing array comparative genomic hybridization and gene expression profiling for transcriptomic analysis. Our results showed that the three cohorts demonstrated diversified clinical features. Ph+ ALL had the best response to induction therapy, with a complete remission (CR) rate of 93.5 and molecular response of 43.5%. Ph+ MPAL had a 90.0% CR rate but only 5.9% of molecular response. The CR rate of Ph+ AML was only 68.8%. Ph+ ALL was characterized by loss and mutations of B-cell development gene IKZF1 and PAX5, and frequent histone H3K36 trimethyltransferase SETD2 mutations. SETD2 mutations were detected in 11.3% of Ph+ ALL patients and predicted higher relapse rate. Ph+ MPAL and Ph+ AML featured high frequency of RUNX1 mutations. Further studies showed RUNX1-R177X mutation inhibited 32D cell differentiation induced by G-Csf, and cooperated with BCR-ABL1 to lead to myeloid differentiation arrest of human cord blood CD34+ cells. It is therefore presumed that these additional mutations work in synergy with BCR-ABL1 fusion gene to facilitate the development of Ph-positive acute leukemia in different immunophenotypic classifications.

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Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification [DAb-seq]

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