| Autor: |
Passet, Marie, Kim, Rathana, Gachet, Stéphanie, Sigaux, François, Chaumeil, Julie, Galland, Ava, Sexton, Thomas, Quentin, Samuel, Hernandez, Lucie, Larcher, Lise, Bergugnat, Hugo, Ye, Tao, Karasu, Nezih, Caye, Aurélie, Heizmann, Beate, Duluc, Isabelle, Chevallier, Patrice, Rousselot, Philippe, Huguet, Françoise, Leguay, Thibaut, Hunault, Mathilde, Pflumio, Françoise, Freund, Jean-Noël, Lobry, Camille, Lhéritier, Véronique, Dombret, Hervé, Domon-Dell, Claire, Soulier, Jean, Boissel, Nicolas, Clappier, Emmanuelle |
| Zdroj: |
Blood; June 2022, Vol. 139 Issue: 24 p3505-3518, 14p |
| Abstrakt: |
Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cisfrom the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4activating mutations. Within adult patients with Ph−B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P= .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P= .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P< .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P= .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3fusion, representing a high-risk disease in young adults. |
| Databáze: |
Supplemental Index |
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