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RNA-sequencing of B-ALL cell lines, REH treated with LNA GapmeRs against four lncRNAs

ABSTRACT: Overwhelming evidence indicates that long non-coding RNAs have essential roles in tumorigenesis. Nevertheless, their expression and role in pediatric B-cell precursor acute lymphoblastic leukemia has not been extensively explored. Here, we conducted a comprehensive analysis of the long non-coding RNA transcriptome in ETV6/RUNX1 positive BCP-ALL, one of the most frequent subtypes of pediatric leukemia. An ETV6/RUNX1 expression signature was established, consisting of 596 lncRNAs (434 up and 162 down) using expression analysis of a series of primary patient samples. Subsequently, RNA sequencing from BCP-ALL cell lines and shRNA-mediated silencing of ETV6/RUNX1, illustrated that lnc-NKX2-3-1, lnc-TIMM21-5, lnc-ASTN1-1 and lnc-RTN4R-1 are bona fide ETV6/RUNX1 targets and could serve as novel biomarkers of this prevalent subtype of human leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79872 | GEO | 2016/09/26

SECONDARY ACCESSION(S): PRJNA317295

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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RNA-sequencing of B-ALL cell lines, REH treated with LNA GapmeRs against four lncRNAs

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