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The cellular hierarchy of acute myeloid leukemia informs personalized treatment

ABSTRACT: The cellular hierarchy of acute myeloid leukemia informs personalized treatment

PROVIDER: PRJNA1137956 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29897100.fastq.gz	Fastqsanger.gz
	SRR29897200.fastq.gz	Fastqsanger.gz
	SRR29897101.fastq.gz	Fastqsanger.gz
	SRR29897201.fastq.gz	Fastqsanger.gz
	SRR29897102.fastq.gz	Fastqsanger.gz

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The cellular hierarchy of acute myeloid leukemia informs personalized treatment

Project description:Acute myeloid leukemia (AML) is characterized by malignant myeloid precursors that span a cellular hierarchy from dedifferentiated leukemic stem cells to mature blasts. While the diagnostic and prognostic importance of AML blast maturation is increasingly recognized, personalized therapies are currently not tailored to a patient’s individual makeup of this cellular hierarchy. In this study, we use multiplexed image-based ex vivo drug screening (pharmacoscopy) to systematically quantify the drug sensitivity across the cellular hierarchy of AML patients. We analyzed 174 prospective and longitudinal patient samples from 44 newly diagnosed AML patients, which indicated that differences in the AML hierarchy significantly identified poor responses to first-line therapy, outperforming European LeukemiaNet (ELN) criteria. Critically, drug response profiling across the AML hierarchy of each patient improved the accuracy of predicting patient response to first-line therapy (AUC 0.91), and revealed alternative individualized treatment options targeting the complete AML hierarchy of non-responding patients. We confirmed these findings in an independent cohort of 26 relapsed/refractory AML patients, for whom pan-hierarchy response profiling improved response predictions post hoc. Overall, our results quantify the clinical importance of therapeutically targeting the complete cellular hierarchy of newly diagnosed AML, and identify multiplexed image-based ex vivo drug screening to enable quantification and targeting of the AML maturation hierarchy for improved personalized treatment.

2024-07-20 | GSE272681 | GEO

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Project description:Paediatric cancers present specific genetic alterations, however the principles underlying their differences to adult cancers are yet unclear. Poor prognosis paediatric myeloid leukaemia fusion oncogenes represent clinically-relevant models to investigate age-specific tumorigenesis. Here, we established an inducible murine model to show that the ETO2-GLIS2 fusion induces both megakaryoblastic and myeloid leukaemia in a cellular and developmental stage-dependent manner, reproducing different age and phenotype associations observed in patients. The aggressive megakaryoblastic leukemia phenotype developed from haematopoietic stem cells and was associated with massive rewiring of master transcription factors activities (e.g. ERG, GATA and CEBPA). Switching off ETO2-GLIS2 expression in transformed cells restored some long-term haematopoietic stem cell potential. In contrast, targeting downstream progenitors was required for the myeloid phenotype. These data demonstrate that the promiscuity between HSC and megakaryocytic states and the ontogenic changes in the cellular architecture of the hematopoietic tissue controls paediatric and phenotype specificities in myeloid leukaemia.

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Elucidation of the phenotypic, functional and molecular topography of a myeloerythroid progenitor cell hierarchy

Project description:The major myeloid blood cell lineages, including erythrocytes, platelets, granulocytes and macrophages, are generated from hematopoietic stem cells (HSC) by differentiation through a series of increasingly more committed progenitor cells. Precise phenotypic identification and functional characterization of such intermediate progenitors has important consequences for understanding fundamental differentiation processes and is clinically relevant since such events become dysregulated in various disease settings, including leukemia. While previous studies have suggested a hierarchy for myeloid differentiation involving a common progenitor through which all myeloid lineages are derived, several recent studies have suggested that such a developmental intermediate might not be an absolute requirement. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin and CD41. Our studies reveal a complex hierarchy of myeloerythroid progenitors with distinct and developmentally restricted lineage potentials. Global gene expression signatures of these cellular subsets revealed expression patterns consistent with their functional capacities, while hierarchical clustering analysis provides details on their lineage relationships. These data challenge existing models of hematopoietic differentiation, by suggesting that progenitors of the innate and adaptive immune system in the adult separate late, and to a large extent, following the divergence of megakaryocytic/erythroid potential. Keywords: global gene expression profiling of prospectively isolated murine bone marrow progenitor subset by usage of affymetrix

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Project description:BackgroundAcute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes.MethodsUsing Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells.ResultsFrom the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic "cancer attractor" that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape.ConclusionsWe identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.

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