The incidence of leukemia is higher in Down syndrome children than that in the general population, while the risk of solid tumors is significantly reduced in Down syndrome. Recent studies utilizing mouse models have shown that distinct mechanisms caused by the elevated dosage of multiple genes is implicated in the protection from tumor progression depending on the type of solid neoplasm. In contrast, increased incidence of mutation in the several specific genes is reported as a cause of the onset of leukemias. Especially, acquired mutations in the GATA1 gene are associated with leukemogenesis of megakaryoblastic leukemia (AMKL) and transient myeloproliferative disorder (TMD) related to Down syndrome. The mutations are clustered in the region corresponding to the N-terminal domain of GATA1 and result in the production of the short form of GATA1 (GATA1-S), which utilizes Met84 as an alternative translation initiation codon. Efforts producing mouse models of Down TMD and AMKL have been undertaken, as these models seem to provide important insights into the pathogenesis of multistep leukemogenesis. Concomitantly, the function of GATA1 has been examined extensively, and the analyses present a prototype for the study of lineage-restricted transcription factors that play an essential role for the differentiation, proliferation, and apoptosis of erythroid cells, megakaryocytes, mast cells, and eosinophils. In this chapter, we will summarize recent progress in the studies of leukemias that occur in Down syndrome, especially in relation to GATA1 mutations.
- Acute megakaryoblastic leukemia
- Acute lymphoblastic leukemia
- Transient myeloproliferative disorder
- Down syndrome
The risk of solid tumors is significantly reduced in Down syndrome (DS) patients compared with the general population [1-3]. Studies utilizing mouse models have shown that distinct mechanisms caused by the elevated dosage of multiple genes are implicated in the protection from tumor progression depending on the type of solid neoplasm. In contrast, DS children have an increased risk of developing leukemias. Specifically, acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL) are approximately 500 and 10-50 times more prevalent in children with DS compared to healthy controls, respectively [4-6].
Recent analyses have uncovered that a distinct pattern of acquired genetic mutations is implicated in the leukemogenesis restricted to DS children. In particular, acquired mutations in the
2. Unique features of leukemias associated with Down syndrome
There are substantial biological differences between the leukemias that occur in DS and non-DS children. It becomes increasingly clear that molecular mechanisms based on trisomy 21 affect not only the high incidence of leukemias but also the characteristic features of DS-associated leukemias.
2.1. DS-associated AMKL
Approximately 5-30% of DS babies are born with a leukocytosis with an erythroid-megakaryocytic immunophenotype. The severity of the clinical course varies with each case, from asymptomatic cases likely to have been considered peaceful births to severe cases resulting in critical injuries with blast cell infiltration of the organs. In severe cases, death from multiorgan failure or hepatic fibrosis is possible, requiring intensive care for the babies. Except for the most severe cases, symptoms usually resolve naturally (Figure 1). Therefore, DS-related leukocytosis is referred to as transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD). Patients suffering from TAM spontaneously achieve complete remission by 6 months of age. While the mechanisms of this spontaneous remission are still under investigation, one recent report showed that type I interferon signaling activated in bone marrow appears to attenuate the hyper-proliferation of megakaryocytes caused by the GATA1-S mutation .
After several years of asymptomatic periods, approximately 20% of DS children with a history of TAM develop genuine AMKL requiring intensive chemotherapy (Figure 1). It has been hypothesized that every DS child first diagnosed with AMKL has a history of asymptomatic TAM at birth. As a result, the incidence of AMKL in DS children is more than 500 times higher than in children without trisomy 21. Thus, this characteristic feature of DS-associated AMKL represents a potentially tractable model of multistep leukemogenesis. Chemotherapy in children with DS-associated AMKL shows a high cure rate. Therefore, the outcome of DS children with AMKL is statistically better than that of AMKL patents without trisomy 21 , probably due to the unique biological characteristics of blast cells. The molecular mechanisms of these remarkable differences remain as yet unknown.
In 2001, it was discovered that somatic mutations on the
Sequential surveys of cases of TAM-AMKL have revealed that the type of
2.2. DS-associated ALL
Acute lymphoblastic leukemia (ALL) is one of the most common malignant diseases in children, and DS children have a higher incidence of this disease than non-DS children. In contrast to the DS-associated AMKL cases, the prognosis of DS-associated ALL is worse than ALL without DS. This may be because DS children are prone to suffer from significant toxicity of chemotherapy, as DS-associated ALL blasts retain high resistance against conventional chemotherapy regimens [16-18]. Intrachromosomal amplification of chromosome 21 (iAMP21) is also recurrently found in pediatric B cell leukemia, and this finding is considered to be an adverse prognostic factor [19, 20]. It has been demonstrated that target genes of the polycom repressor complex 2 (PRC2) are upregulated in both DS-associated ALL and ALL with iAMP21 , indicating that an epigenetic regulation provoked by trisomy 21 is a key mediator of the pathogenesis of this type of leukemia.
Mutations in the developmental genes for B-cell and T-cell lineages are often implicated in the pathogenesis of ALL, irrespective of the presence of Down syndrome. In addition to these genes, the incidence of mutations on genes involving the JAK/STAT pathway and RAS signaling have been found to be increased in DS-associated ALL [22-24], suggesting that molecular changes provided by these mutations may be the reason for the poor survival rate in children with DS-associated ALL.
3. Hematopoiesis in Down syndrome
It has been shown that hematopoietic homeostasis is significantly disturbed in DS fetus . For example, frequencies of hematopoietic stem cells and megakaryocyte-erythroid progenitors are markedly increased showing high clonogenic characteristics, whereas that of granulocyte-macrophage progenitors is reduced [25-27]. In addition, committed pre-proB lymphoid and proB lymphoid progenitors are markedly reduced [25, 26]. This hematological abnormality may be a predominant cause of AMKL and ALL in DS babies. While the hematological abnormalities observed in newborns and infants with DS vary case by case, the following abnormalities are often observed: macrocytosis, neutrophilia, thrombocytopenia, and polycythemia [28-30]. In contrast to the high risk of leukemias in the pediatric period, leukemias are no longer a common cause of death in adults with DS . Instead, macrocytosis and leucopenia are often observed in adult DS cases, leading to the early onset of myelodysplastic syndrome and bone marrow failure .
Strictly speaking, DS is defined by the possession of three copies of DS critical region (DSCR) of human chromosome 21 instead of two. However, the expression of genes located on chromosome 21 or the DSCR in DS patients is not always increased to 1.5-fold that of healthy controls. Depending on the expression levels, genes on human chromosome 21 or DSCR are divided into three categories:
To investigate the contribution of trisomy 21, three groups have independently established iPS (induced pluripotent stem) cells originated from DS patients and analyzed the hematopoietic differentiation. When iPS cells are cultured under the condition of primitive hematopoiesis (the first phase of hematopoiesis in yolk sacs), erythropoiesis is enhanced and myelopoiesis is reduced, while megakaryocytes are normally produced . In contrast, when cultured under the condition of preferentially differentiating into fetal liver–derived definitive hematopoietic cells (the second phase of hematopoiesis in the fetal liver), iPS cells with trisomy 21 show increased multilineage colony-forming potential, and the number of cells with a myeloid and erythroid bipotential phenotype is increased . However, trisomic iPS cells show no difference from isomic iPS cells when they are cultured in a condition suitable to generate erythroblast co-expressing embryonic and fetal globin genes . Thus, the iPS studies suggest that the influence of one extra chromosome 21 to hematopoiesis is altered depending on the hematopoietic microenvironment.
Hematopoietic phenotypes have been examined in multiple lines of DS-model mice. Tc1 mice harbor an aneuploidy, carrying freely segregating human chromosome 21. The Tc1 mice show macrocytic anemia and an increased number of megakaryocytes with extramedullary hematopoiesis in the elderly. On the contrary, significant changes in frequencies of megakaryocytes, erythroid, and myeloid progenitors were not observed in the fetal liver . Ts16 mice were generated by crossing mice with Robertsonian translocation Rb (14;16) and Rb (9;16), resulting in animals trisomic for mouse chromosome 16 (synthetic of human chromosome 21). Ts16 mice show increased erythropoiesis and reduced myelopoiesis during the embryonic period , but defects in hematopoiesis after the neonatal and infantile periods are uncertain, as Ts16 mice do not survive the postnatal period.
Ts65Dn, Tc1Cje, and Ts1Rh mice have been established as lines of euploid DS-model mice bearing a segmented region of mouse chromosome 16 containing 104, 81, and 33 genes, respectively. The Ts65Dn mice suffer from macrocytic anemia with defects of stem cell function and progressive myeloproliferative diseases . In contrast, erythropoiesis is disturbed in Tc1Cje mice, but the mice never develop thrombocytosis or myeloproliferative diseases . Hematopoietic analyses have been performed in Ts1Rhr mice, which are trisomic for the mouse equivalent of the hypothetical human DSCR; these mice show anemia and thrombocytosis in adulthood. Bone marrow cells of the mice preferentially differentiate toward the granulo-monocyte pathway, while the number of B cell progenitors is reduced [21, 43]. During the embryonic stage, hematological abnormalities are not found in Ts1Rhr mice, except for a significant increase in the hematopoietic stem cell population. Although each line of DS-model mice shows partially overlapping hematological phenotypes with those observed in patients with DS, none of the mice develop leukemia or acquire the
GATA1gene mutation in TAM and DS-associated AMKL
GATA1 is a founding member of the GATA family transcription factors that recognize consensus GATA binding motif. In mammals, the hematopoietic GATA subfamily is composed of GATA1, GATA2, and GATA3, which are expressed in erythroid and megakaryocytic cells, hematopoietic stem and progenitor cells, and T cells, respectively . The expressions of GATA1 and GATA2 are partially overlapping, and these two GATA factors regulate the expression of each other. In early erythroid-megakaryocytic progenitors, GATA2 initiates
GATA1 has four functional domains, two transactivation domains in the N- and carboxy (C)-terminal regions and two zinc-finger domains in the middle of body, which are important for the interaction with DNA and multiple cofactors (Figure 3A). Conventional cell-based luciferase reporter assays show that transactivation activity of GATA1-S is reduced into 30% of the full-length of GATA1, which is supported by the function of the C-terminal domain . Functional analyses in mice
Importantly, provability of transformation into AMKL inversely correlates with the expression level of GATA1-S, and the latter is heavily dependent on the type of mutations in
Recently, two types of internally deleted (ID)-type GATA1 proteins were reported as a cause of TAM (Figure 3B) . In the blasts of these cases, aberrant transcripts are produced due to splicing mutations in the
5. Leukemogenesis caused by GATA1 deficiency
These two lines of
However, interestingly, the female
Because simple GATA1-deficiency causes a lethal embryonic phenotype, the roles of GATA1 in adult hematopoiesis are investigated using mice with conditional
An additional line of GATA1-deficient mice (referred to as
We have generated germline
6. Mouse models of TMD and DS-associated AMKL
A transgenic complementation rescue approach has been successfully applied for the investigation of GATA1 function
Exploiting this rescue strategy, we have established transgenic lines of mice expressing GATA1-S. Transgenic expression of GATA1-S rescues the GATA1-deficient males from embryonic lethality . Strikingly, immature megakaryocytes are accumulated in the fetal livers of the rescued mice, but this phenotype disappears after birth , indicating that the simple GATA1-S mutation provokes TMD-like phenotype in mice regardless of the presence of disomy or trisomy of chromosome 16 (the equivalent of human chromosome 21). In a colony-forming assay, progenitors with the GATA1-S mutation produced multiple progenies and generated enormously large colonies, consisting of innumerable immature megakaryocytes that were faintly positive for the AchE staining. In this assay, the number of CFU-Megs in the rescued embryos was equivalent to that in the wild-type embryos. Thus, GATA1-S failed to control proliferation and differentiation during the megakaryocyte differentiation process, resulting in an uncontrolled growth of immature megakaryocytes. It should be noted that TAM appears to be generated by single or a couple of hematopoietic progenitors acquiring the GATA1-S mutation, whereas in the rescued mice, all progenitors express GATA1-S. These observations suggest that the condition provided by trisomy 21 may lead to the onset of TAM by exploiting two pathways: one increases the frequency of GATA1-S mutation, while the other activates cellular mechanisms that magnify the impacts of the GATA1-S mutation.
One of the strong advantages of the transgenic complementation rescue assay is that levels of transgene-derived GATA1-S can be controlled. Because the expression levels of transgene-derived transcript vary between transgenic mouse lines depending on the integrated positions and/or copy numbers of the transgene, transgenic mouse lines expressing high-level GATA1-S and low-level GATA1-S have been used for the rescue analyses. The mice expressing high levels of GATA1-S never develop leukemia, whereas mice expressing low levels of GATA1-S are prone to developing leukemia. The leukemic cells have biphenotypic characteristics of erythroid and megakaryocyte lineages, closely resembling the human DS-associated AMKL (our unpublished observation). Thus, the expression levels of GATA1-S appear to be reflected in the transformation process of TAM blasts to genuine leukemia, consistent with the case of leukemogenesis in the erythroid progenitors of
Mice expressing GATA1 lacking N-terminal 63 amino acids have been established by gene targeting . This line of mice showed transient hyper-proliferation of megakaryocytes in the fetal livers during the early stage of development, whereas the phenotype of the megakaryocytes in the later embryonic stages was close to normal. Because this mutant GATA1 molecule preserves the consensus Rb-binding motif, the effect of GATA1 mutation may be reduced. Another line of mice has been established by second exon deletion (
GATA1 is a lineage restricted transcription factor that is responsible for the hematopoiesis in erythroid and megakaryocyte lineages. GATA1 dysfunction leads to two types of leukemias. One type originates from the
This study was supported in part by grants from JSPS (M.Y.), CREST program of JST and the Mitsubishi Foundation (to M.Y. and R.S.), and Friends of Leukemia Research Fund (R.S.). We also thank Ms. Aya Gotoh and Eriko Naganuma for their help.
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