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

Peretz, Cheryl A.C.; Kennedy, Vanessa E.; Walia, Anushka; Delley, Cyrille L.; Koh, Andrew; Tran, Elaine; Clark, Iain C.; Hayford, Corey E.; D’Amato, Chris; Xue, Yi; Fontanez, Kristina M.; Roy, Ritu; Logan, Aaron C.; Perl, Alexander E.; Abate, Adam R.; Olshen, Adam B.; Smith, Catherine C.

doi:10.1101/2023.05.15.540305

Cited by 2 publications

(1 citation statement)

References 35 publications

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“…Genetically, MPAL often harbor fusions involving BCR::ABL1, KMT2A, ZNF384, BCL11B and PICAML::MLLT10, 12 and mutations in PHF6, DNMT3A, NOTCH1 and WT1. [13][14][15][16][17] In contrast, AML-MRC is enriched for MDS-defining cytogenetic abnormalities and so-called "MR" gene mutations (i.e., SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 with or without RUNX1). 18,19 TP53 mutations and monosomal/complex karyotypes are frequent in t-AML.…”

Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity

Galera,

Dilip,

Derkach

et al. 2023

Preprint

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Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (AML-MP) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MRC and t-AML with MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML-MRC/t-AML without MP. Both AML cohorts with and without MP shared similar clinical features including adverse outcomes but were different from MPAL. The genomic landscape of AML-MP overlaps with AML without MP but differs from MPAL. AML-MP harbors more frequentRUNX1mutations than AML without MP and MPAL.RUNX1mutations did not impact the survival of patients with MPAL. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML-MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML.Key pointsAML-MP clinically and biologically resembles AML but differs from MPAL.AML-MP showsRUNX1mutations, stemness signatures and limited lymphoid lineage plasticity.

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Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity

Galera,

Dilip,

Derkach

et al. 2023

Preprint

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Intrinsic molecular identifiers enable robust molecular counting in single-cell sequencing

Fontanez,

Agam,

Bevans

et al. 2024

Preprint

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Particle-templated instant partition sequencing (PIPseq), is an emerging approach for massively scalable single-cell gene expression studies that does not require complex instrumentation or expensive consumables. We present PIPseq™ V, a novel implementation of the PIPseq workflow with significant improvements in assay performance and sensitivity compared to prior methods. Among the innovations driving the improved performance in PIPseq V is a new approach for transcript counting using Intrinsic Molecular Identifiers (IMIs) from the captured transcript sequence, eliminating the need for traditional Unique Molecular Identifiers (UMIs). IMIs are the starting positions for molecules generated by random fragmentation after limited cycle PCR, which can be used to uniquely identify individual transcript copies of genes expressed within individual cells. To correct for experimental variation in IMI generation, we have developed a dynamic correction strategy that can adapt to different sample cell input, transcript expression, and sequencing depth without the need for external benchmarking or controls. Our results demonstrate that PIPseq V with IMI-based analysis provides biological information comparable to established UMI-based approaches while avoiding UMI-associated biases. Dynamic correction offers a robust and data-driven analysis strategy for scRNAseq.

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

Cited by 2 publications

References 35 publications

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity

Intrinsic molecular identifiers enable robust molecular counting in single-cell sequencing

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