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3D Chromatin Remodeling in B-cell Development and B-cell Acute Lymphoblastic Leukemia [ChIP-seq]

ABSTRACT: The identification of molecular subgroups of B-cell progenitor acute lymphocytic leukemia (B-ALL) have proven to be a powerful tool in understanding the derivation of ALL while also providing essential prognostic information. Several studies have also shown changes in epigenetic landscape including differences across B-ALL subtypes. However, the state of the 3D genome across subtypes and how they compare to healthy B-cell progenitors remains unexplored. Here we use Hi-C and RNA-seq to profile early B-cell progenitors from healthy donors and a number of B-ALL samples harboring the most frequent and prognostic structural variations, including KMT2A::AFF1 and BCR::ABL. We show that B-ALLs undergo subtype-specific changes in 3D genome organization that indicate the differentiation stage of the disease. Additional analysis shows B-ALLs acquire aberrant chromatin configurations and expression of oncogenic drivers compared to normal progenitors. We also find that the TF ERG is aberrantly activated in ETV6::RUNX1 B-ALL, and it aids in the establishment of a differentiation block. Overall, the findings from our study show the impact of altered chromatin folding on the leukemogenic state of B-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243272 | GEO | 2026/03/03

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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3D Chromatin Remodeling in B-cell Development and B-cell Acute Lymphoblastic Leukemia [ChIP-seq]

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