Genomics of TAM

TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive variants involving the GATA1 gene in the presence of trisomy 21.[425,426] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[427]

GATA1 variants are present in most, if not all, children with Down syndrome who have either TAM or acute megakaryoblastic leukemia (AMKL).[425,428-430] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. X-linked GATA1 variants result in the absence of the full-length GATA1 protein, leaving only the normally minor variant, a truncated GATA1s transcription factor that has decreased activity.[425,426] This confers increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly explaining the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[431]

A 2024 analysis screened 143 TAM samples for additional somatic variants in the abnormal cells. With the exception of rare STAG2 variants, the study found no additional abnormalities beyond the typical GATA1 abnormality.[432]

Approximately 20% of infants with TAM and Down syndrome eventually develop AML. Most of these cases are diagnosed within the first 3 years of life.[426,427]

For information about the treatment of TAM, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment.