Chromothripsis is a frequent event and underlies typical genetic changes in early T-cell precursor lymphoblastic leukemia in adults

Abstract

Chromothripsis is a mitotic catastrophe that arises from multiple double strand breaks and incorrect re-joining of one or a few chromosomes. We report on incidence, distribution, and features of chromothriptic events in T-cell acute lymphoblastic leukemias (T-ALL). SNP array was performed in 103 T-ALL (39 ETP/near ETP, 59 non-ETP, and 5 with unknown stage of differentiation), including 38 children and 65 adults. Chromothripsis was detected in 11.6% of all T-ALL and occurred only in adult cases with an immature phenotype (12/39 cases; 30%). It affected 1 to 4 chromosomes, and recurrently involved chromosomes 1, 6, 7, and 17. Abnormalities of genes typically associated with T-ALL were found at breakpoints of chromothripsis. In addition, it gave rise to new/rare alterations, such as, the SFPQ::ZFP36L2 fusion, reported in pediatric T-ALL, deletions of putative suppressors, such as IKZF2 and CSMD1, and amplification of the BCL2 gene. Compared to negative cases, chromothripsis positive T-ALL had a significantly higher level of MYCN expression, and a significant downregulation of RGCC, which is typically induced by TP53 in response to DNA damage. Furthermore we identified mutations and/or deletions of DNA repair/genome stability genes in all cases, and an association with NUP214 rearrangements in 33% of cases.

Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia

“…Cth has also been described in nonsyndromic T-ALL patients with the ETP immunophenotype, but in our cohort, cth was exclusively present in more mature T-cell leukemias (14). Although the clinical features of children with cth pos T-ALL did not substantially differ from those of cth neg ALL, apart from the tendency toward a slower initial response to treatment, 40% of these patients died within a short followup period.…”

“…However, in the majority of blood malignancies, it has been noted in less than 10% of patients, depending on the cth detection method (12). Cth has also been observed in very de ned and rare subtypes of ALL, including ETP-ALL, BCP-ALL with internal ampli cation of chromosome 21 (iAMP21), and T-ALL, which develop in the constitutional background of ataxia telangiectasia (8, 13,14). In adult patients with ETP-ALL, somatic mutations and/or deletions of DNA repair/genome stability genes (BLM, STK11, PTEN, ATM, MUTYH, and ATR) have been found, and up to one-third of these cth cases harbored NUP214 rearrangements (14).…”

Genomic heterogeneity within B/T mixed phenotype acute leukemia in a context of an immunophenotype

“…There are previously underreported and novel genetic alterations in our cohort that merit further discussion. In the two cases of T-lineage predominant B/T MPAL, we identified alterations in STAT5B and SFPQ::ZFP36L2 which have been previously reported in a small subset of T-ALL ( SFPQ::ZFP36L2 being extremely rare) [ 11 , 16 , 17 ] but have not yet been reported in B/T MPAL. Concurrent mutations in RUNX1 and PHF6 along with NOTCH1 mutation indicate an alteration of early hematopoietic differentiation to promote T-cell differentiation at the expense of B-cell differentiation.…”