Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML

Abstract

Acute leukemia is the most frequently diagnosed malignancy in childhood, with acute lymphoblastic leukemia (ALL) comprising approximately 80% of cases in children aged 0-18 years, and acute myeloid leukemia (AML) accounting for approximately 15-20% [1]. The early onset (0-10 years) of most childhood acute leukemias and the high concordance rate among monozygotic twins suggest a prenatal origin of the disease [1]. Indeed, the presence of preleukemic precursors in cord blood (CB) samples or Guthrie blood spots from children who later developed acute leukemia has been demonstrated in several studies [2,3]. However, this has mainly been demonstrated experimentally for the most common cytogenetic subtypes, particularly in ALL.The most prevalent genetic abnormality in infants (up to 1 year of age) with AML (iAML) is chromosome 11q23 translocations involving the KMT2A gene. This occurs at a higher incidence in children than in adults (38% vs 2%), with the highest incidence in infants (77%), suggesting that infant and adult AMLs are distinct biological entities. Notably, iAML may have an in utero origin [4], as demonstrated by long-established evidence of a prenatal origin for MLL rearrangements [5]. In fact, the t(8;21)(q22;q22) AML subgroup has also been associated with a prenatal origin [3]. However, studies of patients with AML in different molecular subgroups have failed to detect the corresponding genetic alteration in the respective CB or Guthrie blood spot samples [6], suggesting a less frequent prenatal origin of AML compared to ALL.The t(7;12)(q36;p13) is a recurrent chromosomal rearrangement uniquely linked to AML. It ranks as the second most common abnormality in infants with AML, constituting nearly one-third of cases and associated with a dismal prognosis [7], with extremely poor survival rates and ineffective treatment by hematopoietic stem cell transplantation. Event-free survival rates (EFS) are 0-14%