Of mice and Down syndrome

Children with Down syndrome (DS) have a 10- to 20-fold higher risk of developing acute leukemia than children without Down syndrome and a 500-fold greater incidence of acute megakaryocytic leukemia (AMkL), highlighting a unique predisposition to develop a specific leukemia subtype. In addition, a small proportion of Down syndrome neonates are born with a variant of AMkL, the transient myeloproliferative disorder (TMD), which can resolve spontaneously, though approximately 20% of these infants will subsequently develop AMkL.

A seminal finding, initially reported from the laboratory of Dr John Crispino and subsequently confirmed by other groups, described acquired somatic mutations in exon 2 of the transcription factor gene GATA1 (localized to Xp11.23) with nearly 100% penetrance in DS TMD and AMkL cases.^1,–3  Sequence alterations in the region encoding the N-terminal activation domain of GATA1 include insertions, deletions, missense, nonsense, and splice-site mutations at the exon 2/intron boundary, resulting in the synthesis of a short-form GATA1 (GATA1s; 40-kDa) protein that exhibits altered transactivation capacity compared with the 50-kDa wild-type protein. GATA1 mutations are believed to represent early or initiating “genetic hits” in a multistep process of leukemogenesis in Down syndrome that can begin prenatally.⁴ 

A new study from the Crispino lab in this issue of Blood continues to contribute to our understanding of the biology of leukemia in children with Down syndrome. Using the Ts65Dn strain of mice, which displays several of the classical features of Down syndrome, including heart defects, cognitive deficits, and craniofacial dysmorphology, Kirsammer and colleagues characterized hematopoiesis in the mice with a series of comprehensive studies. The Ts65Dn mice have trisomy of the distal region of mouse chromosome 16q, estimated to be representative of 94 human chromosome 21-localized genes from the Down syndrome critical region. Among their observations, Kirsammer et al found that the mice had red blood cell macrocytosis (frequently observed in healthy individuals with Down syndrome) and developed thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. Interestingly, GATA1 mutations were not detected in the mice, nor did the mice develop leukemia.

The studies in the Ts65Dn mice suggest that the abnormal hematopoiesis in the mice is linked to overexpression of one or more of the orthologs of human chromosome 21 genes, and this background may prime hematopoietic cells for the development of leukemia. A candidate chromosome 21-localized gene, AML1 (RUNX1), which is linked to the biology of acute leukemias in children and adults, did not appear to be linked to the myelofibrosis and megakaryocyte hyperplasia in the mice.

Narrowing down the field of candidate genes that include the analysis of the oncogene transcription factors ETS2 and ERG, which are also localized to the Down syndrome critical region, is a logical extension of the current studies. We still do not know the linkage of chromosome 21-localized genes and the generation of the GATA1 mutations and whether additional cooperating gene mutations are required. The role of miRNAs, which are down-regulated in megakaryocytic differentiation of CD34⁺ hematopoietic progenitors and up-regulated in AMkL cell lines including the chromosome 21-localized miRNA, miR-99a, requires further analysis, as another important clue in Down syndrome leukemogenesis.⁵ 

Ultimately, studies may identify one or more chromosome 21–localized genes linked to the generation of GATA1 mutations and the development of AMkL and discover whether these genes may also be linked to the extremely high event-free survival rates (> 80%) of Down syndrome AMkL patients.