Short Time Latency in Infant Leukemia with ETV6/RUNX1 fusion Gene

Acute lymphoblastic leukemia (ALL) in infants is characterized by a high frequency of MLL gene rearrangements. By contrast, the ETV6/RUNX1 (TEL/AML1) fusion gene is usually detected in children older than 2 years. In a series of Brazilian infant leukemia cases collected in an epidemiological study, a screening was performed to identify fusion genes found in ALL, we have identified four cases harboring ETV6/RUNX1 in blast cells of infants with 2, 3, 5 and 7 months-old, and common-ALL. To underlie additional genomic hits required to accelerate the emergence of a frank leukemia in these c-ALL cases, we applied the SNP-based genomic copy number analysis, comparing t(12;21) infants with other children with c-ALL in older age-range groups. The presence of ETV6/RUNX1 fusion gene was demonstrated by reverse transcription polymerase chain reaction (RT-PCR) and confirmed by fluorescence in situ hybridization (FISH). All cases were negative for MLL rearrangements, as assessed both by RT-PCR and FISH analyses. As control group (non-leukemic children), we selected 5 samples from children younger than 2 years-old already included in a previous epidemiological study. Infant cases described here present high WBC count (on average 131 × 10⁹/L), and adverse prognosis: two of them relapsed, and one patient only (relapsed) is still alive four years after diagnosis. Recurrent deletions, including 9p21.3 (CDKN2A/2B and MTAP), 11p13 (CD44), 12p13.2 (ETV6) and regions affected by copy number neutral loss of heterozigosity (LOH) were observed. The frequency of genomic deletions and amplifications detected by 100K SNP arrays varied significantly between age-related c-ALL subgroups. The infant leukemia group showed the lower number of chromosome imbalances, whereas the mean number of deletions was similar in the <2 years and 2–10 years age groups, consistent with the observation that the number of gains was largely increasing in older children. It has been postulated that infant leukemia might be caused by transplacental exposures during pregnancy. Then, with these unusual results we have reviewed the data of their mothers’ interviews. Mothers of infants were effectively exposed to a non-steroidal anti-inflammatory drug, and other chemical substances. It may be hypothesize that the pre-leukemic phase in these age-related subgroups of ETV6/RUNX1 positive patients may be evolved with different latencies due to the occurrence of a combination of genetic and environmental factors.