Down syndrome and megakaryocytic leukemia/transient myeloproliferative disorder: when does it begin?

The patterns of malignancy suffered by Down syndrome (DS) children have fascinated oncologists, specifically the 10- to 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) compared with non-DS children, and the reduced susceptibility to developing

The patterns of malignancy suffered by Down syndrome (DS) children have fascinated oncologists, specifically the 10-to 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) compared with non-DS children, and the reduced susceptibility to developing solid tumors, including neuroblastoma and Wilms tumor. AML in DS children displays unique characteristics, including the following: (1) predominance of the megakaryocytic leukemia (AMkL) phenotype and estimated by Zipursky to occur at a 500-fold greater frequency in DS children compared with non-DS children; (2) significantly higher event-free survival rates treated with cytosine arabinoside (ara-C)-based protocols (linked to the chromosome 21-localized gene, cystathionine-␤-synthase [CBS]) compared with non-DS AML patients; and (3) a frequent preceding history of the transient myeloproliferative disorder (TMD), in which blast cells with megakaryocytic antigen expression and morphology are present in peripheral blood and/or bone marrow of DS newborns, that resolves spontaneously with supportive care alone in the majority of cases, though deaths may occur secondary to hepatic fibrosis and/or liver dysfunction.
GATA1 encodes a zinc-finger transcription factor that is essential for normal erythroid and megakaryocytic differentiation. Wechsler et al (Nat Genet. 2002;24:266-270) identified mutations in exon 2 of the GATA1 gene, exclusively in all 6 DS AMkL cases examined compared to a large number of control non-DS AMkL cases. Each of the GATA1 mutations introduced premature stop codons, which would result in the synthesis of a shorter-form GATA1 protein with reduced transactivation activity, potentially affecting normal megakaryocyte differentiation.
In this issue, 2 independent groups reported similar results after analyzing for GATA1 mutations in DS TMD cases. In the study by Mundschau and colleagues (page 4298), all 7 TMD cases, including a DS mosaic case, demonstrated a similar pattern of GATA1 mutations (insertions or deletions in exon 2) as in the previously reported AMkL cases, resulting in premature stop codons, while Hitzler and colleagues (page 4301) detected GATA1 mutations in 3 DS AMkL and 9 TMD cases. In the latter study, the identical GATA1 mutation was identified in blast cells from one child obtained at the time of diagnosis of TMD and when AMkL developed 1 year later, though it was not detected in a subsequent remission bone marrow. The authors of these 2 reports conclude that the acquisition of mutations in the GATA1 gene are early events in the development of TMD and/or AMkL in DS children, although other mutations likely occur for the full expression of the leukemia phenotype.
The presence of identical GATA1 mutations in paired TMD/AMkL blasts provides proof that the TMD clone may not resolve completely, particularly in the 20% to 30% of cases which subsequently develop AMkL, although the TMD clone decreases by unknown mechanisms to a level that is not detected with standard techniques (ie, bone marrow morphology) but may be detectable with more sensitive minimal residual disease techniques.
What role does the presence of 3 copies of chromosome 21 in DS cells and the estimated 225 genes localized to the long arm of the chromosome play in the development of leukemia? The fact that the GATA1 gene is localized to the X chromosome indicates there is interaction of chromosome 21localized genes with genes localized to other chromosomes resulting in leukemogenesis of DS children. It is conceivable that DS children have increased rates of endogenous DNA mutations and/or defects in DNA damage repair. If GATA1 mutations are early events in the development of TMD/AMkL, are there healthy DS children harboring GATA1 mutations who do not develop AML? Since GATA1 mutations in TMD cases develop in utero, do all GATA1 mutations arise in utero even in DS AMkL cases with no preceding history of TMD? This possibility could be examined in the future utilizing newborn screening cards (Taub et al, Blood. 2002;99:2992-2996 or umbilical cord blood samples. (Mori et al, Proc Natl Acad Sci U S A. 2002;99:8242-8247). Additional studies should provide insights as to why the GATA1 gene appears uniquely susceptible for the acquisition of mutations in DS children and the mechanisms leading to the full expression of the AMkL phenotype after the acquisition of GATA1 mutations.

TFPI and venous thrombosis
Tissue factor pathway inhibitor (TFPI) plays a critical role in the regulation of tissue factorinduced blood coagulation. This has been corroborated by gene knock-out experiments in mice and TFPI immunodepletion experiments in rabbits challenged with tissue factor. Numerous clinical studies, however, have been unable to establish an association between low TFPI levels and venous thrombosis.
Dahm and colleagues (page 4387) evaluated cases and controls from the Leiden Thrombophilia Study and found that low TFPI levels are a significant, albeit weak, risk factor for a first episode of deep venous thrombosis. The relationship was strongest for free TFPI but was also found for total TFPI antigen and activity. Measuring TFPI is a complex undertaking given that there are free and bound plasma pools of the inhibitor, as well as the presence of a large endothelial-associated pool, which may be the most important pool from a physiologic standpoint. The latter pool, however, is difficult to evaluate clinically, although it can be assessed following its release into the plasma by heparin.
A major confounding variable in studies 4228 BLOOD, 1 JUNE 2003 ⅐ VOLUME 101, NUMBER 11