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PAX5-Inherited susceptibility causes leukemia by conferring sensitivity to DNA damage in preleukemic B cells

ABSTRACT: We used microarrays to analyze gene expression changes in leukemic bone marrow cells from Pax5+/- and WT mice, comparing them with preleukemic bone marrow precursor B cells from both genotypes. All mice were exposed to a single low-dose irradiation (2 Gy). PAX5 is a master regulator of B-cell development, and germline mutations in PAX5 predispose individuals to B-cell acute lymphoblastic leukemia (B-ALL). While PAX5 alterations are a hallmark of B-ALL, the mechanisms linking inherited susceptibility to leukemic transformation remain poorly understood. Here, we provide in vivo genetic evidence demonstrating that reduced Pax5 dosage increases sensitivity to DNA damage, acting as a key factor in B-ALL initiation. Using a mouse model of Pax5 heterozygosity, we show that exposure to a single low-dose irradiation (2 Gy) significantly accelerates leukemia onset, establishing a direct link between genetic predisposition and environmental stress. Notably, the resulting murine B-ALLs closely resemble the human disease, exhibiting complete Pax5 loss, CD19 downregulation, and a high incidence of DNA double-strand breaks. Mechanistically, we identify Pax5 as a regulator of p53-mediated DNA damage responses in preleukemic B cells, highlighting its role beyond lineage specification. These findings provide a mechanistic framework for the interplay between PAX5 deficiency, genomic instability, and environmental factors in early B-ALL development, uncovering new potential vulnerabilities for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE291995 | GEO | 2025/03/19

REPOSITORIES: GEO

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Project description:ETV6-RUNX1 is associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequence of ETV6-RUNX1 expression on cell lineage decision during B-cell leukemogenesis remains largely evasive. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but only a few carriers develop B-ALL as a result of the acquisition of secondary postnatal genetic hits, like KDM5C or PAX5 loss. However, understanding the mechanism involved in this transformation would advance the development of non-toxic prophylactic interventions to preleukemic carriers. Using genetic lineage tracing, we have examined the capacity of ETV6-RUNX1 in instructing a B-cell malignant phenotype. Restricted Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 locus into B-cell precursors does not trigger B-ALL development. Similarly, concomitant transient ETV6-RUNX1 expression in hematopoietic progenitors close to restricted Cre-mediated introduction of second hit (Kdm5c loss) in B-cells fail to induce B-ALL. In contrast, targeting ETV6-RUNX1 in hematopoietic progenitors was required to induce leukemia. These mice develop either T-ALL or B-ALL, suggesting that the nature of the second hit may define tumor cell identity during ETV6-RUNX1 leukemogenesis. In order to uncover a potential exclusive effect of the second hit in establishing the leukemic phenotype, we next showed that the introduction of the second hit, either Kdm5c or Pax5 loss, to the ETV6-RUNX1 preleukemic clone confers the tumor B-cell identity without need of environmental infection exposure. The resulting B-ALLs clustered according to the second-hit by RNA sequencing (RNA-Seq) analysis. Together these results provide a novel paradigm for the generation of tumor B cells through ETV6-RUNX1 in vivo where the second hit confers the tumor cell-identity to the ETV6-RUNX1 preleukemic clone. These findings could be relevant to develop new therapeutic approaches to prevent disease development.

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PAX5-Inherited susceptibility causes leukemia by conferring sensitivity to DNA damage in preleukemic B cells

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