Genetic abnormalities identified in leukemia associated SD.
Constitutional trisomy 21 or Down syndrome (DS) is the most common human genetic aneuploidy caused by the presence of all or part of an extra 21 chromosome. The incidence of DS is estimated at 1 per 700 births (Malinge et al., 2009) and is the most common genetic factor predisposing to childhood leukemia. People with DS present several clinical phenotypes, including cognitive impairment, craniofacial dysmorphy, gastrointestinal tract abnormalities, congenital heart defects, endocrine abnormalities, neuropathology leading to dementia and immunological defects. Concerning the hematopoietic system, children with DS frequently show abnormalities in platelet counts, macrocytosis and an increased prevalence of leukemia (Lange, 2000; Roizen & Amarose, 1993).
2. Manifestations of leukemia in Down Syndrome
The high frequency of leukemia in children with DS suggests that trisomy 21 is involved directly and functionally to the malignant transformation of hematopoietic cells. However, DS is not a classic genomic instability syndrome, since the overall risk of developing cancer, in particular solid tumors, including neuroblastoma and Wilms tumor, is lower in these people (Hasle, 2001; Malinge et al., 2009).
Newborns with DS have a risk 10 to 20 times higher of developing acute leukemia (AL) when compared with the incidence rates of leukemia in the general child population (Hitzler et al., 2003). The AL in children with DS presents an intriguing relationship between the age at onset of disease and the subtype of leukemia cell. DS children older than 4 years have predominantly acute lymphoblastic leukemia (ALL), whose incidence is approximately 20 times higher than in the general population. However the DS patients aged under 3 years are more likely to develop acute megakaryoblastic leukemia (AMKL), with an incidence 500 times higher than in children without DS(Hitzler et al., 2003; Issacs, 2003; Lange, 2000; Malinge et al., 2009).
The condition of patients with DS awakens, therefore, a special interest in studies on leukemogenesis not only by the high prevalence of AMKL, usually rare in the general pediatric population, but also by another form of clonal proliferation called transient myeloproliferative disorder (TMD) which affects between 5 and 10% of newborns with DS. The TMD is a clonal disease characterized by accumulation of immature megakaryoblasts in fetal liver and peripheral blood, a picture indistinguishable from AL (Hitzler et al., 2003; Malinge et al., 2009; Pine et al., 2007; Rainis et al., 2003; Zipursky, 2003). It is unclear whether all AMKLs are preceded by TMD, since several TMD cases are underdiagnosed. One study suggests that the prognosis for AMKLs preceded by TMD is better than de novo AMKL (Klusmann et al., 2008).
In contrast to AMKL, TMD usually evolves to spontaneous remission within the first three months of life and therefore is considered a pre-leukemic syndrome. This spontaneous remission can vary from 59 to 64% (Kanezaki et al., 2010; Massey et al., 2006). However, approximately 20% of children diagnosed with TMD will develop AMKL after 2 to 3 years of TMD spontaneous remission, which does not regress without chemotherapy (Malinge et al., 2009).
The biological mechanism of TMD spontaneous remission is not clear. Holt et al. (2002) showed that telomerase activity was decreased at the beginning of congenital leukemia and suggested that this deficiency could explain the spontaneous regression. Furthermore, the factors underlying the transformation of the TMD "benign" status for "evil" in AMKL are unknown (Izraeli et al., 2007; Malkin et al., 2000; Rainis et al., 2003).
In rare cases, the TMD is fatal due to poor prognostic factors such as liver fibrosis or liver dysfunction, manifested by jaundice, bleeding diathesis, fetal hydrops, cardiopulmonary failure, high white blood cell (WBC) and failure of spontaneous remission within the first 3 months (Malinge et al., 2009; Massey et al., 2006; Pine et al., 2007; Shimizu et al., 2008). Most of these variants were found in all reports. However, the risk factors for the progression to AMKL remain unclear (Kanezaki et al., 2010). Three studies in the United States, Japan and Europe reported the natural course of TMD in 264 children with DS. These studies confirmed the transient course of this disease that usually resolved spontaneously within the first 3 months of life. However, these studies revealed that the disease is not benign, since early deaths have been reported in 15 to 20% of the cases (Klusmann et al., 2008; Massey et al., 2006; Muramatsu et al., 2008). Kanezaki et al. (2010) also reported early death in 24.2% of the DS patients with TMD.
3. Mutations in
GATA1 gene and leukemogenesis in Down Syndrome
The analysis of megakaryocyte-specific knockdown of
Studies have shown that
Somatic mutations in the N-terminus activation domain of
The expression levels of GATA-1 isoforms are crucial for the proper development of erythroid and megakaryocytic cells and compromised GATA-1 expression is a causal factor in leukemia (Shimizu et al., 2008). These findings strongly suggest that the qualitative deficit of GATA-1 contributes to the genesis of TMD and AMKL (Kanezaki et al., 2010). The selection of mutations that retain GATA-1s may result in disruption of normal balance between GATA-1 and GATA-1s, which probably would be involved in regulating normal development of megakaryocytes (Izraeli et al., 2007), but pass to act as an oncogene directly in the presence of trisomy 21. Alternatively, GATA-1s may be required for survival of leukemic blasts and the oncogenic effect may be purchased by the loss of the heavy chain of GATA-1. Another possibility is that this type of mutation may reflect specific mechanisms of selection or generation of this mutation in the presence of trisomy 21 (Rainis et al., 2003).
According some evidences the arising of AL is due to the cooperation between one class of mutations which interferes with differentiation (class II mutations) and another class which confers a proliferative advantage to cells (class I mutations) (Deguchi & Gilliland, 2002). It has been shown that high level expression of exogenous GATA-1 lacking the N-terminus induced differentiation rather than decreased the aberrant growth of GATA1-null megakaryocytes (Kuhl et al., 2005; Muntean & Crispino, 2005). This observation suggested that abundant GATA-1s functions like a class I mutation in TMD blasts. In contrast, reducing GATA-1 expression leads to differentiation arrest and aberrant growth of megakaryocytic cells (Vyas et al., 1999). The present data suggest that GATA-1s is expressed at very low levels in TMD blasts with GATA-1s low mutations. These levels may not be sufficient to provoke normal maturation. Together, these findings suggest that the low expression of GATA-1s might function like class II mutations in TMD blasts. Additional class I mutations or epigenetic alterations might be more effective in the development of leukemia in blast cells expressing GATA-1s at low levels (Kanezaki et al., 2010).
Rainis et al. (2003) reported two patients with identical
Wechsler et al. (2002) analyzed the X chromosome inactivation in cell lysates from BM of women carrier from AMKL. Since the female leukemic cells showed the X chromosome inactivation due to monoclonality, and the mutant allele was detected only in leukemic cells, they predicted that the wild-type allele should be on the inactive X chromosome. As expected, only the truncated protein GATA-1s was observed. On the other hand Rainis et al. (2003) proposed that if there was no process of X chromosome inactivation,
Ahmed et al. (2004) described for the first time multiple independent
GATA-1s is no different from wild type in their ability to bind to DNA and interact with its co-factor friend of GATA-1(FOG-1), but shows a reduction in their ability to transcriptional activation since it was truncated to its activation domain N-terminal (Rainis et al., 2003; Wechsler et al., 2002).
FOG-1 binds specifically to the NF zinc finger motif of GATA-1, and is expressed abundantly in erythroid and megakaryocytic cells (Crispino et al., 1999). FOG-1 is encoded by the gene
A missense mutation in the
4. Other mutations associated with DS leukemia
The occurrence of mutations in exon 2 of
Based on numerous studies with mutations in
The identification of activating mutations in tyrosine kinase genes in TMD and AMKL specimens has provided new insights into the evolution of AMKL.
|Types of leukemia||Mutated gene||Localization||Frequencies recorded|
5. Trisomy 21 influence on hematopoiesis
The functional contribution of the trisomy 21 in hematologic malignancies is supported by several observations such as the high incidence of leukemia in DS patients, the fact that TMD and AMKL blasts present trisomy 21 (even in children without DS), and that acquired trisomy or tetrasomy of chromosome 21 is frequently observed in blasts of different types of leukemia, including hyperdiploid ALL and de novo AML (Vyas & Crispino, 2007).
It is assumed that the cells of DS complete or partial trisomy of Hsa21, approximately 33.7 Mb, promote an overexpression of at least one of the 364 known genes, 31 antisense transcripts, and five different miRNAs (miR-99a, let-7c, miR-155, miR-125b-2, and miR-802), which could cooperate with the loss of GATA-1 in the pathogenesis of AMKL. Mutations in several genes on chromosome 21 have been identified in leukemia, and many of them recognized as encoding transcription factors acting at various stages of hematopoiesis. There should be contribution of genes present on chromosome 21 that cooperate with mutations of the
The identification of the Down Syndrome Critical Region (DSCR) on the 21q22 band based in the genotype-phenotype correlations of partial trisomy in children suspected of having DS disclosed a list of genes potentially implicated in the clinical phenotype. However no specific genes have been certainly linked to the increased incidence of leukemia in DS. Few strong candidates include
Since the TMD is originated in a fetal liver progenitor and is restricted to children with DS (or to rare cases of acquired trisomy 21), it is presumed that trisomy 21 directly affects the development of hematopoietic cells during gestation. It has been shown that
The functional perturbations induced by trisomy 21 probably induce a highly susceptible cellular environment to additional transformations such as
6. Specific chromosome 21 genes in DS-associated leukemia
Two microarray studies comparing AMKL versus non-DS AML have recently been reported (Bourquin et al., 2006; Ge et al., 2006) and 76 genes were described that discriminate between DS AMKL and non-DS. For example, genes encoding erythroid markers, glycophorin A and CD36, were found meaningly overexpressed in AMKL, as conﬁrmed by immunophenotypic analysis of blasts (Langebrake et al., 2005).
Analysis of the gene expression data also revealed that there is an overall increase in expression of chromosome 21 genes in AMKL, relative to non-DS AMKL. By gene set enrichment analysis, 47 Hsa21 genes, including
6.1. Candidate leukemia oncogenes encoded by chromosome 21
Of the genes on chromosome 21, several are compelling candidate leukemia oncogenes. Of these, four such candidates are
Inherited hypomorphic mutations in
In different types of cancer, it has been shown that the
The ETS family member
6.2miRNAs encoded by chromosome 21
Hsa21 encode five miRNAs and overexpression of some of these has been observed in brain and heart tissues of people with DS and has been implicated in normal and pathologic hematopoiesis (Kuhn et al., 2008). For example, miR-99a is up-regulated during megakaryocytic differentiation of CD34+ cells, whereas miR-155 and let-7c are down-regulated (Garzon et al., 2006). Notably, miR-155 has been linked to myeloproliferative and B-lymphoproliferative disorders (Garzon & Croce 2008; O’Connell et al., 2008). Studies have implicated miR-125b-2, which is overexpressed in TMD and AMKL samples compared with normal megakaryocytes, in the megakaryocytic leukemia of DS (Klusmann, 2007).
Klusmann et al. (2010) showed that miR-125b-2 is an oncogene potentially involved in the pathogenesis of trisomy 21-associated leukemia. They demonstrated in mice and human that overexpression of miR-125b-2 led to specific hyperproliferation and enhanced self-renewal capacity of megakaryocytic progenitor (MPs) and megakaryocytic/erythroid progenitors (MEPs), without affecting their normal differentiation. The miR-125b was highly expressed in AMKL blasts, whereas the identified target genes of miR-125b were down-regulated. Thus, miR-125b-2 has a role in regulating megakaryopoiesis and in the pathogenesis of trisomy 21-associated TMD and AMKL, in cooperation with GATA1s. The miR-125b-2 exerts its oncogenic potential by at least two different mechanisms: blocking post-transcriptional miRNA processing through repression of
7. Methods of leukemia diagnosis in DS
The diagnosis of TMD usually occurs during the first weeks after birth and is observed as hydrops fetalis. The elevated blood count associated with hepatomegaly is the common symptom in an asymptomatic neonate. Infants with TMD can also display occasionally jaundice and bleeding diatheses, respiratory distress coupled with ascites, pleural effusion, signs of heart failure, and skin inﬁltrates. There is megakaryocytic inﬁltration and liver ﬁbrosis, likely caused by excess cytokines secreted from the megakaryoblasts. The full clinical TMD may develop only at the second or third week of life. Laboratory tests are signiﬁcant for either thrombocytosis or thrombocytopenia accompanied by elevated leukocytes with excess of blasts. The blood smear may show nucleated red cells, giant platelets and megakaryocytic fragments, and, most signiﬁcantly, typical deeply basophilic blasts with blebs characteristic to megakaryocytic blasts. The differential diagnosis includes leukoerythroblastic reaction associated with prematurity, sepsis, or asphyxia. However, the blasts of TMD usually persist for several weeks, and
AMKL is preceded in 20 to 60% of cases by an indolent prephase of myelodysplasia (MDS), characterized by thrombocytopenia and dysplastic changes, BM aspiration is often dry, and ﬁbrosis is detected in BM biopsy (Creutzig et al., 1996; Lange et al., 1998). This MDS can last several months or years before progressing to leukemia. In contrast to MDS in non-DS children, which requires stem-cell transplantation for cure, MDS in children with DS present a highly favorable response to chemotherapy alone (Lange et al., 1998). Therefore, Hasle et al. (2003) suggested that all cases of MDS and overt myeloid leukemia in DS, children should be classified as one disease entity, and referred to as ‘‘acute myeloid leukemia of Down syndrome’’ or ML DS. As this is a unique disease, it should be classified separately from other cases of AML in the WHO-classification.
Immunophenotyping characterizes the hematopoietic lineage involved and their degree of maturation by monoclonal antibodies labeled with fluorochromes. Flow cytometry reveals that blasts are positive for CD34, CD33, CD41, CD61, glycophorin A, and often CD7 and CD36 (Langebrake et al., 2005, Massey et al., 2006). Savasan & Ravindranath (2003) observed that blasts of DS children with AMKL express CD36, in contrast to the low or no expression of CD36 in AML without DS. If 25% of blast cells are not detected, the diagnosis of AMKL can be given by the megakaryocytic markers CD41, CD61 and CD42a. The immunophenotype of the blasts in AMKL is generally similar to TMD, except that the percentage of CD34 cells may be lower in AMKL (Langebrake, 2005; Malinge et al., 2009).
Pine et al. (2005) demonstrate the possibility of using specific
This approach serves as a valuable tool in monitoring the spontaneous remission of TMD and in assessing response to treatment of AMKL subcytologic level. In addition, the MRD based GATA-1s mutations has been much in demand as a prognostic parameter for newborns with TMD. One may speculate, for example, that every group of newborns showing apparent remission of TMD can be divided into two subgroups: one in which the size of the clone of blasts in TMD after morphological remission continues to decline to become undetectable versus a second group, in which a clone of blasts in the TMD remains detectable submicroscopic level. It is interesting to correlate these patterns of MRD kinetics in TMD with the probability of developing AMKL later (Hitzler & Zipursky, 2005).
Additional copies of chromosome 8 and 21 in addition to the constitutional trisomy 21 are the most frequent in AMKL, and are found in approximately 10 to 15% for each chromosome. Cytogenetic findings associated with a high rate of relapse in non-DS AML, such as monosomy 7 and deletion 5/5q- also occur in DS patients but do not seem to have a negative impact on prognosis in the rare cases (Gamis et al., 2003, 2005; Rainis et al., 2003).
The approach of molecular techniques including: PCR amplification of
Until recently, there were no reports on the expression levels of GATA-1s in TAM blasts, and the risk factors for the progression to AMKL. In 2010, Kanezaki et al. tested whether the spectrum of transcripts derived from the mutant
Nevertheless, neither mice nor humans with germline mutations expressing GATA-1s develop TMD or AMKL without trisomy 21 (Hollanda et al., 2006; Li et al., 2005). Therefore, the role of the trisomy 21 in the cellular transformation in AMKL seems to be fundamental (Klusmann et al., 2010).It remains unknown which factors on chromosome 21 cooperate with the oncogenic GATA-1s and which factors are involved in this transition from preleukemia to AMKL in only a part of these children (Kanezaki et al., 2010; Klusmann et al., 2007; Langebrake et al., 2006; Malinge et al., 2009).
8. Treatment outcome
DS children with AMKL have an excellent prognostic, with an approximately 80% cure rate, in relation to children without DS who develop AML (Arico et al.; 2008; Creutzig et al., 2005; Gamis et al., 2003; Rao et al., 2006; Taub et al., 1996). This outcome is possible on contemporary AML protocols which based in reducing treatment intensity regimens has considerably reduced the mortality rates in children with DS (Creutzig et al., 2005; Gamis et al., 2003; Whitlock et al., 2005; Zeller et al., 2005).
AMKL blasts have shown hypersensitivity to varied chemotherapeutic drugs (Zwaan et al., 2002). Probably the hypersensibility of the blasts to cytarabine (ARA-C) is due of the effect of
Researchs in prospective clinical trials are trying to demonstrate whether treatment of TMD by low-dose cytarabine could prevent the arise of AMKL. Another related question to be clarified is whether treatment of clinically silent disease, identiﬁed by molecular detection of
In conclusion, many questions remain unanswered concerning the factors that contribute to the progression of TMD and AMKL in DS-patients. Progress in research to unravel these questions will improve diagnosis and treatment. Furthermore, ensuring the diagnosis of
Review supported by CAPES – Project CEP-FM 34/2008 and SES-DF 339/08.
Ahmed M. Sternberg A. Hall G. Thomas A. Smith O. O’marcaigh A. Wynn R. Stevens R. Addison M. King D. Stewart B. Gibson B. Roberts I. Vyas P. 2004Natural history of GATA1 mutations in Down syndrome., 103 7 2480 2489, 0006-4971
Arico M. Ziino O. Valsecchi M. G. et al. 2008Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of PediatricHematology and Oncology (AIEOP). 113 3 515 521, 0000-8543X
Baldus C. D. Liyanarachchi S. Mrozek K. et al. 2004Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: ampliﬁcation discloses overexpression of APP, ETS2, and ERG genes. , 101 11 3915 3920, 0027-8424
Bourquin J. P. Subramanian A. Langebrake C. et al. 2006).Identiﬁcation of distinct molecular phenotypes in acute megakaryoblasticleukemia by gene expression proﬁling.Proceedings of the National Academy of Sciences of the United States of America, 103 103 9 3339 3344, 0027-8424
Calligaris R. Bottardi S. Cogoi S. Apezteguia I. Santoro C. 1995Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. 92 25 11598 11602, 0027-8424
Chou S. T. Opalinska J. B. Yao Y. et al. 2008Trisomy 21 enhances human fetalerythro-megakaryocytic development. 112 12 4503 4506, 0006-4971
Creutzig U. Ritter J. Vormoor J. et al. 1996).Myelodysplasia and acute myelogenousleukemia in Down’s syndrome.A report 4040 children of the AML-BFM Study Group., 10 11 1677 1686, 0887-6924
Creutzig U. Reinhardt D. Diekamp S. Dworzak M. Stary J. Zimmermann M. 2005 AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. , 19 8 1355 1360, 0887-6924
Crispino J. D. Lodish M. B. Mackay J. P. Orkin S. H. 1999). Use of altered specificity mutants to probe a specific protein-protein interaction in differentiation: the. , 1FOG complex 3 2 219 228, 1097-2765
De Vita S. Mulligan C. Mc Elwaine S. et al. 2007Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome. 137 4 337 341, 0007-1048
Deguchi K. Gilliland D. G. 2002Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML. , 16 4 740 744, 0887-6924
Fox A. H. Liew C. Holmes M. Kowalski K. Mackay J. Crossley M. 1999Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. 18 10 2812 2822, 0261-4189
Gamis A. S. Woods W. G. Alonzo T. A. et al. 2003Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children’s Cancer Group Study 2891., 21 18 3415 3422, 0073-2183X
Gamis A. S. 2005Acute myeloid leukemia and Down syndrome evolution of modern therapy-state of the art review., 44 1 13 20, 1545-5009
Garzon R. Pichiorri F. Palumbo T. et al. 2006MicroRNA ﬁngerprints during human megakaryocytopoiesis.Proceedings of the National Academy of Sciences of the United States of America, 103 13 5078 5083, 0027-8424
Garzon R. Croce C. M. 2008MicroRNAs in normal and malignant hematopoiesis. 15 4 352 358, 1065-6251
Ge Y. Stout M. L. Tatman D. A. et al. 2005GATA1, cytidinedeaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. , 97 3 226 231, 0027-8874
Ge Y. Dombkowski A. A. La Fiura K. M. et al. 2006Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia.Blood, 107 1570 1581, 0006-4971
Ge Y. La Fiura K. M. Dombkowski A. A. et al. 2008).The role of the proto-oncogene 2in acute megakaryocytic leukemia biology and therapy., 22 3 521 529, 0887-6924
Gjertson C. Sturm K. S. Berger C. N. 1999).Hematopoietic deﬁciencies and core binding factor expression in murine 16an animal model for Down syndrome. 91 1 50 60, 0174-4666X
Groet J. Mulligan C. Spinelli M. Serra A. Mcelwaine S. Cotter F. E. Dagna-Bricarelli F. Saglio G. Basso G. Nizetic D. 2005Independent clones at separable stages of differentiation, bearing different GATA1 mutations, in the same TMD patient with Down syndrome. 106 5 1887 1888, 0006-4971
Hasle H. 2001Pattern of malignant disorders in individuals with Down’s syndrome., 2 7 429 436, 1470-2045
Hasle H. Niemeyer C. M. Chessells J. M. et al. 2003A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. 17 2 277 282, 0887-6924
Hitzler J. K. Cheung J. Li Y. Scherer S. W. Zipursky A. 2003GATA1 mutations in transient leukemia and acute megakaryoblasticleukemia of Down syndrome.Blood, 101 11 4301 4304, 0006-4971
Hitzler J. Zipursky A. 2005GATA 1 mutations as clonal markers of minimal residual disease in acute megakaryoblasticleukemia of Down syndrome--a new tool with significant potential applications.Leukemia Research, 29 11 1353 1356, 0145-2126
Hollanda L. M. Lima C. S. Cunha A. F. Albuquerque D. M. Vassallo J. Ozelo M. C. Joazeiro P. P. Saad S. T. Costa F. F. 2006An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. 38 7 807 812, 1061-4036
Holt S. E. Brown E. J. Zipursky A. 2002).Telomerase and the benign and malignant megakaryoblasticleukemias of Down syndrome. 24 24 1 14 17, 0192-8562
Issacs H. 2003Fetal and neonatal leukemia. 25 5 348 361, 0192-8562
Izraeli S. 2004Leukemia: a developmental perspective. 126 1 3 10, 0007-1048
Izraeli S. Rainis L. Hertzberg L. Smooha G. Birger Y. 2007). Trisomy of chromosome 21in leukemogenesis. 39 2 156 159, 0000-1079- 9796
Kanezaki R. Toki T. Terui K. Xu G. Wang R. Shimada A. Hama A. Kanegane H. Kawakami K. Endo M. Hasegawa D. Kogawa K. Adachi S. Ikeda Y. Iwamoto S. Taga T. Kosaka Y. Kojima S. Hayashi Y. Ito E. 2010Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. , 116 22 4631 4638, 0006-4971
Kirsammer G. Jilani S. Liu H. et al. 2008).Highly penetrant myeloproliferative disease in the 65mouse model of Down syndrome. 111 2 767 775, 0006-4971
Klusmann J. H. Reinhardt D. Hasle H. et al. 2007).Janus kinase mutations in the development of acute megakaryoblasticleukemia in children with and without Down’s syndrome. 21 21 7 1584 1587, 0887-6924
Klusmann J. H. Creutzig U. Zimmermann M. et al. 2008).Treatment and prognostic impact of transient leukemia in neonates with Down syndrome., 111 111 6 2991 2998, 0006-4971
Klusmann J. H. Li Z. Böhmer K. Maroz A. Koch M. L. Emmrich S. Godinho F. J. Orkin S. H. Reinhardt D. 2010miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblasticleukemia. , 24 5 478 490, 0890-9369
Kuhl C. Atzberger A. Iborra F. Nieswandt B. Porcher C. Vyas P. 2005GATA1-mediated megakaryocyte differentiation and growth control can be uncoupled and mapped to different domains in GATA1. 25 19 8592 8606, 1098-5549
Kuhn D. E. Nuovo G. J. Martin M. M. et al. 2008Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts. , 370 3 473 477, 0000-6291X
Lange B. J. Kobrinsky N. Barnard D. R. et al. 1998Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. , 91 2 608 615, 0006-4971
Lange B. J. 2000The management of neoplastic disorders of hematopoiesis in children with Down’s syndrome. 110 3 512 524, 0000-0007- 1048
Langebrake C. Creutzig U. Reinhardt D. 2005).Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs signiﬁcantly from other diseases with morphologically identical or similar blasts., 217 217 3 126 134, 0300-8630
Langebrake C. Klusmann J. H. Wortmann K. Kolar M. Puhlmann U. Reinhardt D. 2006Concomitant aberrant overexpression of RUNX1 and NCAM in regenerating bone marrow of myeloid leukemia of Down’s syndrome., 91 11 1473 1480, 0390-6078
Levanon D. Groner Y. 2004).Structure and regulated expression of mammalian RUNX genes., 23 23 24 4211 4219, 0950-9232
Li Z. Godinho F. J. Klusmann J. H. Garriga-Canut M. Yu C. Orkin S. H. 2005Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1., 37 6 613 619, 1061-4036
Look A. T. 2002A leukemogenic twist for GATA1. 32 1 83 84, 1061-4036
Loughran S. J. Kruse E. A. Hacking D. F. et al. 2008The transcription factor Erg is essential for deﬁnitive hematopoiesis and the function of adult hematopoietic stem cells. , 9 7 810 819, 1529-2908
Lyle R. Bena F. Gagos S. et al. 2009).Genotype-phenotype correlations 30Down syndrome identiﬁed by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. 17 4 454 466, 1018-4813
Malinge S. Izraeli S. Crispino J. D. 2009).Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. 113 113 12 2619 2628, 0006-4971
Malkin D. Brown E. J. Zipursky A. 2000).The role 53p53 in megakaryocytic differentiation and the megakaryocytic leukemias of Down syndrome. 116 1 1 5, 0165-4608
Marcucci G. Baldus C. D. Ruppert A. S. et al. 2005Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. 23 9234 9242, 0073-2183X
Martin D. I. Orkin S. H. 1990Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1. , 4 11 1886 1898, 0890-9369
Massey G. V. Zipursky A. Chang M. N. et al. 2006A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. 107 12 4606 4613, 0006-4971
Mundschau G. Gurbuxani S. Gamis A. S. Greene M. E. Arceci R. J. Crispino J. D. 2003Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. 101 11 4298 4300, 0006-4971
Muntean A. G. Crispino J. D. 2005Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development. 106 4 1223 1231, 0006-4971
Muramatsu H. Kato K. Watanabe N. et al. 2008).Risk factors for early death in neonates with Down syndrome and transient leukemia. 142 142 4 610 615, 0007-1048
Nichols K. E. Crispino J. D. Poncz M. White J. G. Orkin S. H. Maris J. M. Weiss M. J. 2000Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. 24 3 266 270, 1061-4036
O’Connell R. M. Rao D. S. Chaudhuri A. A. et al. 2008Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. , 205 3 585 594, 0022-1007
Osato M. Asou N. Abdalla E. et al. 1999).Biallelic and heterozygous point mutations in 1runt domain of the AML1 gene associated with myeloblasticleukemias. , 93 6 1817 1824, 0006-4971
Pang L. Xue H. H. Szalai G. et al. 2006).Maturation stage-speciﬁc regulation of megakaryopoiesis by pointed-domain Ets proteins., 108 108 7 2198 2206, 0006-4971
Pine S. R. Guo Q. Yin C. et al. 2005GATA1 as a new target to detect minimal residual disease in both transient leukemia and megakaryoblasticleukemia of Down syndrome.Leukemia Research, 29 11 1353 1356, 0145-2126
Pine S. R. Guo Q. Yin C. Jayabose S. Druschel C. M. Sandoval C. 2007).Incidence and clinical implications 1GATA1 mutations in newborns with Down syndrome. 110 6 2128 2131, 0006-4971
Preudhomme C. Warot-Loze D. Roumier C. et al. 2000High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. 96 8 2862 2869, 0006-4971
Rainis L. Bercovich D. Strehl S. et al. 2003Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. , 102 3 981 986, 0006-4971
Rainis L. Toki T. Pimanda J. E. et al. 2005The protooncogene ERG in megakaryoblasticleukemias.Cancer Research, 65 17 7596 7602, 0008-5472
Rao A. Hills R. K. Stiller C. et al. 2006Treatment for myeloid leukemia of Down syndrome: population based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. 132 5 576 583, 0007-1048
Roizen N. J. Amarose A. P. 1993).Hematologic abnormalities in children with Down syndrome. 46 46 5 510 512, 1552-4868
Savasan S. B. S. Ravindranath Y. 2003Cd36 Expression Is Associated With Superior In Vitro Ara-C Sensitivity In Acute Megakaryocytic Leukemia With And Without Down Syndrome., 41 10 274 275, 0109-6911X
Shimizu R. Takahashi S. Ohneda K. Engel J. D. Yamamoto M. 2001).In vivo requirements for 1 functional domains during primitive and definitive erythropoiesis., 20 18 5250 5260.
Shimizu R. Kuroha T. Ohneda O. et al. 2004).Leukemogenesis caused by incapacitated 1function. , 24 24 10814 10825, 1098-5549
Shimizu R. Engel J. D. Yamamoto M. 2008).GATA1-related leukaemias., 8 8 4 279 287, 0147-4175X
Taub J. W. Matherly L. H. Stout M. L. Buck S. A. Gurney J. G. Ravindranath Y. 1996Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. 87 8 3395 3403, 0006-4971
Taub J. W. Huang X. Ge Y. et al. 2000Cystathionine-beta-synthase cDNA transfection alters the sensitivity and metabolism of 1-beta-D-arabinofuranosylcytosine in CCRF-CEM leukemia cells in vitro and in vivo: a model of leukemia in Down syndrome. Cancer Research, 60 22 6421 6426, 0008-5472
Taub J. W. Mundschau G. Ge Y. et al. 2004Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. , 104 5 1588 1589, 0006-4971
Tunstall-Pedoe O. Roy A. Karadimitris A. et al. 2008Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. , 112 12 4507 4511, 0006-4971
Vyas P. Ault K. Jackson C. W. Orkin S. H. Shivdasani R. A. 1999Consequences of GATA-1 deficiency in megakaryocytes and platelets.Blood, 93 9 2867 2875, 0006-4971
Vyas P. Crispino J. D. 2007Molecular insights into Down syndrome-associated leukemia., 19 1 9 14, 1040-8703
Walters D. K. Mercher T. Gu T. L. et al. 2006Activating alleles of JAK3 in acute megakaryoblasticleukemia. 10 1 65 75, 1535-6108
Wang Z. Burge C. B. 2008Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. 14 5 802 813, 1355-8382
Wechsler J. Greene M. Mc Devitt M. A. Anastasi J. Karp J. E. Le Beau M. M. Crispino J. D. 2002Acquired mutations in GATA1 in the megakaryoblasticleukemia of Down syndrome. 32 1 148 152, 1061-4036
Weiss M. J. Yu C. Orkin S. H. 1997Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. , 17 3 1642 1651, 1098-5549
Whitlock J. A. Sather H. N. Gaynon P. et al. 2005Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. 106 13 4043 4049, 0006-4971
Xu G. Nagano M. Kanezaki R. et al. 2003Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome., 102 8 2960 2968, 0006-4971
Yang Z. F. Mott S. Rosmarin A. G. 2007The Ets transcription factor GABP is required for cell-cycle progression. 9 3 339 346, 1097-6256
Yu C. Niakan K. K. Matsushita M. Stamatoyannopoulos G. Orkin S. H. Raskind W. H. 2002).X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of 1affecting DNAbinding rather than FOG-1 interaction., 100 6 2040 2045, 0006-4971
Zeller B. Gustafsson G. Forestier E. et al. 2005Acute leukaemia in children with Down syndrome: a population-based Nordic study. 128 6 797 804, 0007-1048
Zipursky A. 2003Transient leukemia: a benign form of leukemia in newborn infants with trisomy 21. 120 6 930 938, 0007-1048
Zwaan C. M. Kaspers G. J. Pieters R. et al. 2002).Different drug sensitivity proﬁles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. 99 99 1 245 251, 0006-4971