In Utero Origins of Acute Leukemia in Children

de Smith, Adam J.; Spector, Logan G.

doi:10.3390/biomedicines12010236

Cited by 3 publications

References 92 publications

(111 reference statements)

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

Bousquets-Muñoz,

Molina,

Varela

et al. 2024

Leukemia

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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%

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

Bousquets-Muñoz,

Molina,

Varela

et al. 2024

Leukemia

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Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia

Liu,

Xu,

Pardeshi

et al. 2024

Preprint

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Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13–5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination.

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Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review

Djulejic,

Ivanovski,

Cirovic

et al. 2024

JPM

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The preventability of acute lymphocytic leukemia during childhood is currently receiving great attention, as it is one of the most common cancers in children. Among the known risk factors so far are those affecting the development of gut microbiota, such as a short duration or absence of breastfeeding, cesarean section, a diet lacking in short-chain fatty acids (SCFAs), the use of antibiotics, absence of infection during infancy, and lack of pets, among other factors. Namely, it has been shown that iron deficiency anemia (IDA) and lack of vitamin D may cause intestinal dysbiosis, while at the same time, both increase the risk of hematological malignancies. The presence of IDA and vitamin D deficiency have been shown to lead to a decreased proportion of Firmicutes in stool, which could, as a consequence, lead to a deficit of butyrate. Moreover, children with IDA have increased blood concentrations of cadmium, which induces systemic inflammation and is linked to the onset of an inflammatory microenvironment in the bone marrow. Finally, IDA and Cd exposure increase fibroblast growth factor 23 (FGF23) blood levels, which in turn suppresses vitamin D synthesis. A lack of vitamin D has been associated with a higher risk of ALL onset. In brief, as presented in this review, there are three independent ways in which IDA increases the risk of acute lymphocytic leukemia (ALL) appearance. These are: intestinal dysbiosis, disruption of vitamin D synthesis, and an increased Cd load, which has been linked to systemic inflammation. All of the aforementioned factors could generate the appearance of a second mutation, such as ETV6/RUNX1 (TEL-AML), leading to mutation homozygosity and the onset of disease. ALL has been observed in both IDA and thalassemia. However, as IDA is the most common type of anemia and the majority of published data pertains to it, we will focus on IDA in this review.

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In Utero Origins of Acute Leukemia in Children

Cited by 3 publications

References 92 publications

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

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

Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia

Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review

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