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Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

ABSTRACT: Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

PROVIDER: PRJNA996892 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28983740_1.fastq.gz	Fastqsanger.gz
	SRR28983740_2.fastq.gz	Fastqsanger.gz
	SRR28983741_1.fastq.gz	Fastqsanger.gz
	SRR28983741_2.fastq.gz	Fastqsanger.gz
	SRR28983742_1.fastq.gz	Fastqsanger.gz

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Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

Project description:Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible transcription factor to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) transcription factor to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 years of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated towards CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established a novel transcription factor that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable transcription factors have the potential to be applied as molecular tools to produce functional immune cells for cell therapy.

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