Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

Abstract

GATA-1 is the founding member of a transcription factor family that regulates growth and maturation of a diverse set of tissues. GATA-1 is expressed primarily in hematopoietic cells and is essential for proper development of erythroid cells, megakaryocytes, eosinophils, and mast cells. Although loss of GATA-1 leads to differentiation arrest and apoptosis of erythroid progenitors, absence of GATA-1 promotes accumulation of immature megakaryocytes. Recently, we and others have reported that mutagenesis of GATA1 is an early event in Down syndrome (DS) leukemogenesis. Acquired mutations in GATA1 were detected in the vast majority of patients with acute megakaryoblastic leukemia (DS-AMKL) and in nearly every patient with transient myeloproliferative disorder (TMD), a "preleukemia" that may be present in as many as 10% of infants with DS. Although the precise pathway by which mutagenesis of GATA1 contributes to leukemia is unknown, these findings confirm that GATA1 plays an important role in both normal and malignant hematopoiesis. Future studies to define the mechanism that results in the high frequency of GATA1 mutations in DS and the role of altered GATA1 in TMD and DS-AMKL will shed light on the multistep pathway in human leukemia and may lead to an increased understanding of why children with DS are markedly predisposed to leukemia. IntroductionThe incidence of leukemia in children with Down syndrome (DS) is 1 in 100 to 200, which is 10-to 20-fold higher than in children without DS. Although in non-DS children lymphoid neoplasms comprise most of the leukemias arising in this age group, half of the leukemias in DS are myeloid. Children with DS exhibit a 46-fold excess incidence of acute myeloid leukemia (AML), with acute megakaryoblastic leukemia (AMKL) accounting for at least 50% of these cases. 1 In addition to acute leukemia, children with DS are also predisposed to developing the related transient myeloproliferative disorder (TMD). At least 10% of infants with DS develop TMD, a disease in which immature megakaryoblasts accumulate in liver, bone marrow, and peripheral blood; this disorder undergoes spontaneous remission in most cases. [2][3][4] Of note, approximately 30% of DS infants with TMD develop AMKL within 3 years. 1 TMD blasts are morphologically indistinguishable from AMKL blasts, contributing to the hypothesis that the second disease is derived from the first. 5,6 Often the karyotype of the AMKL blasts is more complex than that of the TMD, but contains abnormalities observed in the original TMD clone, consistent with clonal evolution. [7][8][9][10][11] Classified as FAB M7 subtype, these blasts exhibit classical ␣-naphthyl acetate esterase activity with a multifocal punctate cytoplasmic staining pattern that is only partially inhibited by sodium fluoride. 12 Immunophenotyping shows that the blasts express the myeloid markers CD33 and CD13, in addition to at least one platelet-associated antigen (CD36, CD41a, CD41b, or CD61). A proportion of these blasts also express erythroid-specific mRNAs, such as...

Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

“…A dosage effect of candidate oncogenic genes from chromosome 21 has been invoked as a contributor to DS-AMKL pathogenesis (7,18,19). We detected BACH1 among the chromosome 21 genes whose expression is highly represented in DS-AMKL.…”

“…These mutations occur at early times in hematopoietic tissues during development. AMKL blasts express both erythroid and megakaryocytic markers, a finding that suggests transformation of an erythroid͞megakaryocyte precursor of fetal origin (6,7). In mice, loss of GATA1 causes maturation arrest and sustained proliferation of megakaryocyte precursors (8).…”

Abnormalities of GATA-1 in Megakaryocytes from Patients with Idiopathic Myelofibrosis

“…Among CMPDs, IM is characterized by well-defined and specific alterations in the proliferation and differentiation of megakaryocytes. Mutations in the GATA-1 gene have recently been associated with inherited 40 and acquired 41 human pathologies that present defective megakaryocytopoiesis; the latter include the transient myeloproliferative disorder of the newborn, the megakaryoblastic leukemia of Down syndrome, and at least a sporadic case of megakaryoblastic leukemia. 42 These diseases are also characterized by a conspicuous BM fibrosis that accompanies the proliferation of abnormal megakaryocyte precursors.…”

Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice

“…We used the GATA-1 HRD promoter because GATA-1 is a key transcription factor in the differentiation of both erythrocytes and megakaryocytes (Shivdasani et al, 1997), which are two sublineages in a fraction of myeloid lineage cells, and mutations in this gene are associated with DS-AMKL, one of the intriguing case where an increased dose of RUNX1 is possibly implicated in leukemogenesis (Wechsler et al, 2002;Gurbuxani et al, 2004). RT-PCR and Western blotting showed that whole bone marrow (BM) cells from Runx1 Tg mice overexpressed Runx1 by roughly fivefold above wild-type (WT) mouse level ( Figure 1a).…”

“…Recent studies employing retrovirus insertional mutagenesis showed that integration into the promoter region of Runx1 results in overexpression of the gene and induces murine T-cell lymphomas (Wotton et al, 2002). In addition, an extra copy of RUNX1 on chromosome 21 has been suspected to be responsible for the increased risk for Down's syndrome (DS) children to develop leukemia, since the minimum region on chromosome 21 that causes DS contains the RUNX1 locus (Dufresne-Zacharia et al, 1994;Antonarakis, 1998;Reeves et al, 2001;Gurbuxani et al, 2004). Infants with DS frequently develop transient abnormal myelopoiesis (TAM) and subsequent acute megakaryoblastic leukemia (AMKL).…”