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Case Report: Rare IKZF1 gene fusions identified in neonate with congenital KMT2A-rearranged Acute Lymphoblastic Leukemia

ABSTRACT: Here we describe a rare case of congenital KMT2Ar ALL presenting with co-occurring IKZF1 gene fusions and a predictably aggressive disease trajectory. We report for the first time, the novel IKZF1::TUT1 and KDM2A::IKZF1 gene fusions. Rearrangements in-volving KMT2A are commonly retained in relapsed infant ALL, however, in this case the KMT2A::AFF1 gene fusion did not appear to be the lesion driving leukemic relapse. Instead, our data suggest that relapse was driven by IKZF1::TUT1. This gene fusion remained in all samples investigated, including the on-blinatumomab therapy sample taken immediately prior to relapse. Conversely, the KMT2A::AFF1 gene fusion was only detected in the diagnosis and refractory post-induction samples highlighting a key role for IKZF1::TUT1 in disease pathogenesis. Intriguingly, both IKZF1 gene fusions are predicted to be out-of-frame, however, our data demonstrate the IKZF1 gene is still expressed. This is not unprecedented and it has previously been observed that out-of-frame fusions can cause transcriptional activation/repression of genes involved in the fusions leading to increases or decreases of their expression and the as-sociated functional outcomes.

PROVIDER: EGAS00001006947 | EGA |

REPOSITORIES: EGA

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Project description:Background Children with Down Syndrome have an augmented risk for B-cell acute lymphoblastic leukaemia (DS-ALL), which is associated with a survival lower than in non-DS ALL, due to increased chemotherapy-related toxicity and a higher relapse rate, thus demanding new tailored therapeutic strategies. Cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while alterations in CRLF2 and IKZF1 genes are increased. Aim of the study was to evaluate in DS-ALL children the incidence and prognostic value of the Philadelphia Chromosome-Like (Ph-like) status and the “IKZF1plus” profile, both associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols for BCP-ALL. Method Seventy DS-ALL patients at diagnosis treated in Italian centres from 2000 to 2014 were evaluated for their cytogenetic status, including the Ph-like ALL profile, while the IKZF1plus feature was investigated in a larger cohort of 134 patients treated in Italian and German centres from 2000 to 2011. Findings Forty-six out of 70 (65•7%) AIEOP DS-ALL patients displayed the Ph-like ALL gene expression signature, mostly characterized by CRLF2 (n=33) and IKZF1 (n=16) alterations (13 had both alterations); only one case was positive for an ABL-class and one for a PAX5 fusion gene. In the Italian and German joint cohort, we observed 35•6% patients positive for P2RY8::CRLF2 fusion, 24•8% for IKZF1 deletion and 18% for IKZF1plus feature. Unexpectedly, a higher IKZF1 expression and activity were observed in IKZF1plus than IKZF1 wt DS-ALL patients. Ph-like signature and IKZF1 deletion were associated with poor outcome, which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition. Interpretation These subgroups, which for the most part are not associated with other high risk features, need new and tailored therapeutic strategies, not only focussed on the use of drugs that restore IKZF1 function.

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Case Report: Rare IKZF1 gene fusions identified in neonate with congenital KMT2A-rearranged Acute Lymphoblastic Leukemia

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