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Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

ABSTRACT: Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p < 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p < 0.001).

SUBMITTER: Mangum DS

PROVIDER: S-EPMC9852218 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Mangum David Spencer DS Bishop Johnathon D JD Zhou Yinmei Y Cheng Cheng C Karol Seth E SE Rubnitz Jeffrey E JE Ribeiro Raul C RC Yang Jun J JJ Mullighan Charles G CG Jeha Sima S Pui Ching-Hon CH Inaba Hiroto H

British journal of haematology 20221109 3

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patient ...[more]

PMID: 36352514

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Project description:Purpose: To investigate metabolic adaptation of leukaemia in two different microenvironments: central nervous system and spleen Methods: The SEM (MLL-AF4) cell-line representing a high-risk subtype was used. Cells were transplanted into immunodeficient mice. CNS tropism was demonstrated and blasts invaded the leptomeninges in a timeframe ranging from 4 to 5 weeks. At experimental endpoint, blasts were retrieved from the CNS and periphery (spleen), and their gene expression profiles were compared using RNA-sequencing. The raw reads were pre-processed with Cutadapt v.1.5 and Sickle v.0.940 software. Transcript expression quantification was performed using Kallisto v.0.42.4 software against combined human and mouse transcriptomes, Ensembl GRCh38.79 and GRCm38.78, respectively. Read counts related to human transcripts were collected, rounded, and summarized into gene specific read counts. Gene-based differential expression analysis was done with DESeq2 R-package. Preprocessed RNA expression data from RNA sequencing was analysed further using single sample gene set enrichment analysis (ssGSEA). Results: The human SEM cells’ gene expression profiles clustered according to site of colonization in the transplanted mice; CNS versus spleen. The top differentially expressed genes were associated with cellular metabolism or stress responses. ssGSEA analysis identified positive correlation of lipid and lipoprotein metabolism signatures in CNS-derived cells, with particular propensity towards fatty acid synthesis. On the other hand, oxidative phosphorylation processes, linked to fatty acid degradation, were negatively correlated with CNS involvement and enriched in SEM cells from the spleen of transplanted mice. Conclusions: We demonstrate that leukaemic cells undergo widespread dynamic rewiring of metabolism when switching from bone marrow to CNS microenvironments, resulting in altered therapeutic vulnerabilities. We observed a strong fatty-acid synthesis signature in CNS leukaemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player.

Project description:Purpose: To investigate metabolic adaptation of leukaemia in two different microenvironments: central nervous system and spleen Methods: The REH (TEL-AML1) cell line representing a standard-risk subtype was used. Cells were transplanted into immunodeficient mice. CNS tropism was demonstrated and ALL blasts invaded the leptomeninges in a timeframe ranging from 4 to 5 weeks. At experimental endpoint, blasts were retrieved from the CNS and periphery (spleen), and their gene expression profiles were compared using RNA-sequencing. The raw reads were pre-processed with Cutadapt v.1.5 and Sickle v.0.940 software. Transcript expression quantification was performed using Kallisto v.0.42.4 software against combined human and mouse transcriptomes, Ensembl GRCh38.79 and GRCm38.78, respectively. Read counts related to human transcripts were collected, rounded, and summarized into gene specific read counts. Gene-based differential expression analysis was done with DESeq2 R-package. Preprocessed RNA expression data from RNA sequencing was analysed further using single sample gene set enrichment analysis (ssGSEA). Results: The human REH cells’ gene expression profiles clustered according to site of colonization in the transplanted mice; CNS versus spleen. Top differentially expressed genes were associated with cellular metabolism or stress responses. ssGSEA analysis identified positive correlation of lipid and lipoprotein metabolism signatures in CNS-derived cells, with particular propensity towards fatty acid synthesis. On the other hand, oxidative phosphorylation processes, linked to fatty acid degradation, were negatively correlated with CNS involvement and enriched in REH cells from the spleen of transplanted mice. Conclusions: We demonstrate that leukaemic cells undergo widespread dynamic rewiring of metabolism when switching from bone marrow to CNS microenvironments, resulting in altered therapeutic vulnerabilities. We observed a strong fatty-acid synthesis signature in CNS leukaemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player.

Dataset Information

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Publications

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Similar Datasets

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