Leukemia is a major cause of death in children (<10 years) who have Down syndrome (DS). DS occurs at a rate of 1 in 1000 births, and patients exhibit a 10- to 20-fold elevated risk of developing acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL).1,2 The risk of developing solid tumors, such as lymphomas, is lower, because trisomy 21 acts as a protective barrier. Genes (e.g., COL18A1, DSCR-1, ETS2) located on chromosome 21 effectively inhibit tumors as a result of this gene dosage effect.1

Children with DS account for about 2% of the total ALL population in children.1 Lower event-free survival rates, and higher treatment-associated toxicity and mortality are typically observed in DS-ALL patients.2 Cytogenetically, these patients show a lower frequency TEL/AML1, an over-expression of JAK2,1 genomic aberrations (e.g., +X, t(8:14), del(9p))3, and increased expression of CRLF2, as well as DNA damage response genes (e.g., BCL6).4,5

Acute myeloid leukemia in DS children accounts for up to15% of childhood AML.3 The cytogenetic profile of DS-AML children differs from DS-ALL, and includes trisomies 8, 11, 21, dup(1p), dup(7q), del(6q), del(7p) and del(16q).1,3 The frequent occurrence of trisomies in DS-AML indicates nondisjunction events in cell division.3 Transient myeloproliferative disorder (TMD) occurs in 10% of DS newborn children where megakaryoblasts are detected in the bone marrow or peripheral blood. TMD occurs only in cases with trisomy 21.1,2 Approximately 20 to 30% of TMD patients progress to DS-AMKL. Acute megakaryocytic leukemia (AMKL) is a common subtype of DS-AML, observed in children (<4 years) with a 500-fold incidence rate.1,6,7 Distinct clonal mutations in GATA1, a transcription factor commonly observed in DS-AML, arise during the progressive transformation of TMD to AMKL.7 A recent study has shown GATA1 mutations cooperate with a microRNA overexpressed on chromosome 21 (miR-125b-2) to enhance progression to AMKL.8 Somatic mutations of GATA1 modifies response to therapy. Children with DS-AML also show increased sensitivity to therapeutic agents (e.g., ara-C, daunorubicin).1

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Attempts to identify genes responsible for leukemogenesis in DS patients can elucidate the pertinent pathway involved, enabling targeted therapy with lower toxicity. The prevalent research consensus is that there appears to be a distinct tumorigenic pathway in DS-leukemia.