What question did this study set out to answer?

To determine how monoallelic versus biallelic TP53 mutations distinctively affect genomic stability, transcriptional programs, and self-renewal in human hematopoietic stem and progenitor cells.

August 20, 2026LeukemiaOpen Access

Mutant TP53 allelic states in human hematopoietic stem and progenitor cells

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Authors

KLK. LindMedical University of Graz SDSayantanee DuttaMedical University of Graz MCMarco Raffaele CosenzaEuropean Molecular Biology Laboratory

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Implication

Preclinical study reveals that monoallelic TP53 mutations trigger chromosomal instability while biallelic loss drives self-renewal in human HSPCs, highlighting early intervention targets.

Key Points

To determine how monoallelic versus biallelic TP53 mutations distinctively affect genomic stability, transcriptional programs, and self-renewal in human hematopoietic stem and progenitor cells.
Engineered monoallelic (R175H/WT, R273H/WT, KO/WT) and biallelic (R175H/KO, R273H/KO, KO/KO) TP53 genotypes in human umbilical cord blood CD34+ HSPCs using CRISPR/Cas9 and AAV6-mediated knock-in.
Evaluated clonogenic self-renewal with methylcellulose colony-forming unit and serial replating assays.
Profiled genomic instability and gene expression using single-cell template strand sequencing and RNA sequencing under baseline and doxorubicin-stress conditions.
Biallelic TP53-aberrant HSPCs demonstrated sustained colony-forming capacity through serial replating assays, whereas monoallelic and wild-type control cells exhausted clonogenic growth after three passages.
Monoallelic TP53 mutations significantly elevated chromosomal aberration rates under doxorubicin stress (with spontaneous increases in R175H variants) and upregulated immune checkpoint ligand PD-L1 and inflammatory pathways.
Biallelic TP53 loss specifically induced overexpression of the homeobox factor HOXA10 and down-regulated mitotic spindle and G2/M checkpoint gene sets.

Cite This Study

Lind et al. (2026) studied this question.

synapsesocial.com/papers/6a86b57f8a91293e6a1ccf0b https://doi.org/10.1038/s41375-026-03106-x

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Implication

Preclinical study reveals that monoallelic TP53 mutations trigger chromosomal instability while biallelic loss drives self-renewal in human HSPCs, highlighting early intervention targets.

Mutant TP53 allelic states in human hematopoietic stem and progenitor cells

Discussion

Member takes

Implication

Key Points

Cite This Study

Mutant TP53 allelic states in human hematopoietic stem and progenitor cells

Discussion

Member takes

Implication

Key Points

Cite This Study

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