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Reconstruction of Human AML Using Functionally and Immunophenotypically Defined Human Haematopoietic Stem and Progenitor Cells as Targeted Populations

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numbere4262
JournalBio-protocol
Volume11
Issue number24
DOIs
Published20 Dec 2021

Bibliographical note

Funding Information: This study was supported by Cancer Research UK, Blood Cancer UK, Kay Kaydall Leukaemia Research Fund and TBRS RGC HK. This protocol is based on and used in a recent report (Zeisig et al., 2021; DOI: 10.1126/scitranslmed.abc4822). Publisher Copyright: © 2021 The Authors.

King's Authors

Abstract

Acute myeloid leukaemia (AML) is a highly heterogenous blood cancer, in which the expansion of aberrant myeloid blood cells interferes with the generation and function of normal blood cells. Although key driver mutations and their associated inhibitors have been identified in the last decade, they have not been fully translated into better survival rates for AML patients, which remain dismal. In addition to DNA mutation, studies in mouse models strongly suggest that the cell of origin, where the driver mutation (such as MLL fusions) occurs, emerges as an additional factor that determines the treatment outcome in AML. To investigate its functional relevance in human disease, we have recently reported that AML driven by MLL fusions can transform immunophenotypically and functionally distinctive human hematopoietic stem cells (HSCs) or myeloid progenitors resulting in immunophenotypically indistinguishable human AML. Intriguingly, these cells display differential treatment sensitivities to current treatments, attesting the cell of origin as an important determinant governing treatment outcome for AML. To further facilitate this line of investigation, here we describe a comprehensive disease modelling protocol using human primary haematopoietic cells, which covers all the key steps, from the isolation of immunophenotypically defined human primary haematopoietic stem and progenitor populations, to oncogene transfer via viral transduction, the in vitro liquid culture assay, and finally the xenotransplantation into immunocompromised mice.

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