期刊
BLOOD
卷 139, 期 24, 页码 3505-3518出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021014723
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资金
- Association Laurette Fugain
- La Ligue regionale du Haut-Rhin Contre le Cancer
- Institut National du Cancer [PLBIO 19-289]
- ITMO Cancer of Aviesan Cancer Control Strategy
- THEMA, the national center for precision medicine in leukemia
A novel subtype of B-cell acute lymphoblastic leukemia (B-ALL) characterized by CDX2 cis-deregulation and UBTF::ATXN7L3 fusion was identified in young adults, showing poor response to treatment and high risk of relapse. This subtype represents a high-risk disease entity in adults with unique genetic alterations.
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::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2 , located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating 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::ATXN7L3 fusion, representing a high-risk disease in young adults.
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