Curr Hematol Malig Rep DOI 10.1007/s11899-016-0338-x MYELOPROLIFERATIVE DISORDERS (C HARRISON, SECTION EDITOR) Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update Neha Bhatnagar1 & Laure Nizery2 & Oliver Tunstall3 & Paresh Vyas4 & Irene Roberts5 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Children with constitutional trisomy 21 (Down Introduction syndrome (DS)) have a unique predisposition to develop my- eloid leukaemia of Down syndrome (ML-DS). This disorder Population studies show that children with Down syndrome is preceded by a transient neonatal preleukaemic syndrome, due to constitutional trisomy 21 have a markedly increased transient abnormal myelopoiesis (TAM). TAM and ML-DS risk of developing acute leukaemia compared with children are caused by co-operation between trisomy 21, which itself without Down syndrome [1]. Both myeloid leukaemia, known perturbs fetal haematopoiesis and acquired mutations in the as myeloid leukaemia of Down syndrome (ML-DS), and acute key haematopoietic transcription factor gene GATA1.These lymphoblastic leukaemia are increased by 150- and ∼30-fold, mutations are found in almost one third of DS neonates and respectively [1, 2]. ML-DS has a distinct natural history and are frequently clinically and haematologcially ‘silent’.While clinical and biological features (reviewed in [3, 4]). It virtually the majority of cases of TAM undergo spontaneous remission, always develops before the age of 5 years, and the acute leu- ∼10 % will progress to ML-DS by acquiring transforming kaemia is preceded by a clonal neonatal preleukaemic syn- mutations in additional oncogenes. Recent advances in the drome known as transient abnormal myelopoiesis (TAM) that unique biological, cytogenetic and molecular characteristics is unique to Down syndrome [3, 4]. of TAM and ML-DS are reviewed here. TAM is characterised by increased circulating blast cells that harbour acquired N-terminal truncating mutations in the key haematopoietic transcription factor gene GATA1 [5–10]. Keywords Transient abnormal myelopoiesis . Down Around 10–15%ofneonateswithDownsyndromehavea syndrome . Acute leukaemia . Myeloproliferative disorders diagnosis of TAM with blasts >10 % and typical clinical fea- This article is part of the Topical Collection on Myeloproliferative Disorders * Irene Roberts 1 Children’s Hospital, John Radcliffe Hospital, Oxford University [email protected] Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK Neha Bhatnagar 2 Paediatric Intensive Care Unit, Robert Debré Hospital, 48 Boulevard [email protected] Sérurier, 75019 Paris, France Laure Nizery 3 Bristol Royal Hospital for Children, Paul O’Gorman Building, Upper [email protected] Maudlin St, Bristol BS2 8B, UK Oliver Tunstall 4 Molecular Haematology Unit, Weatherall Institute of Molecular [email protected] Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK Paresh Vyas [email protected] 5 Department of Paediatrics, Children’s Hospital, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK Curr Hematol Malig Rep tures that require close monitoring in the neonatal period since particular ERG and DYRK1a, as important mediators of the mortality rate may be up to 20 %. A further 10–15 % of the abnormal megakaryopoiesis, although this does not neonates with Down syndrome have one or more acquired seem to be sufficient to cause leukaemia in trisomic or GATA1 mutations in association with a low number of circu- disomic mouse models even when co-expressed with an lating blast cells (<10 %) and have clinically and N-terminally truncated GATA1 gene. Interestingly, recent haematologically silent disease (silent TAM) [11••]. In the data using a panel of iPSC lines, suggest that trisomy of majority of cases of TAM and silent TAM, the GATA1 mutant RUNX1, ETS2,andERG might be sufficient, in combina- clone goes into complete and permanent remission without the tion with mutant GATA1, to explain many of the need for chemotherapy. However, 10–20 % of neonates with haematopoietic abnormalities seen in primary human fetal TAM and silent TAM subsequently develop ML-DS in the liver and TAM cells. Despite these interesting findings, it first 5 years of life when persistent GATA1 mutant cells ac- is now clear that trisomy 21 causes genome-wide changes quire additional oncogenic mutations, most often in cohesin or in gene expression directly or indirectly affecting multiple epigenetic regulator genes [12••, 13]. This review article dis- genes on most chromosomes [23]. cusses the recent clinical and biological advances in TAM and (ii) N-terminal truncating GATA1 mutations in TAM and ML-DS and how these may impact on clinical management. ML-DS The link between acquired mutations in the GATA1 Cellular and Molecular Pathogenesis of TAM and ML-DS gene and ML-DS was first identified more than 12 years ago in John Crispino’slab[5] and rapidly followed by The cellular and molecular events involved in initiation and studies from a number of groups confirming the link with evolution of TAM and ML-DS can best be understood as a trisomy 21 as well as showing the same N-terminal trun- three-step model which requires the presence within a fetal cating mutations in TAM [6–10]. The GATA1 mutations liver-derived haematopoietic stem or progenitor cell of (i) tri- that can be detected in all cases disappear when TAM somy 21, (ii) an acquired GATA1 mutation, and (iii) at least (or ML-DS) enter remission indicating that these are ac- one additional oncogenic mutation (Fig. 1). quired events [9, 12••]. Application of highly sensitive next-generation sequencing (NGS)-based methodology (i) Perturbation of fetal haematopoiesis by trisomy 21 has recently shown that GATA1 mutations are present The initial event in trisomy 21-associated preleukaemic in all cases of TAM or ML-DS and that they are present and leukaemic conditions is the perturbation of fetal in 25–30 % of all neonates with Down syndrome [11••]. haematopoiesis by trisomy 21 itself. It is known that by This means that GATA1 mutations are necessary for the late in the first trimester of fetal life, haematopoiesis in the development of TAM/ML-DS, that they are acquired pri- liver is abnormal in fetuses with trisomy 21 and that these or to birth in fetal cells and that they occur at an aston- changes precede the acquisition of GATA1 mutations ishingly high frequency. It seems likely that acquisition [14, 15••]. Specifically, trisomy 21 causes an increase in of such mutations confers a selective growth advantage the numbers of megakaryocyte-erythroid progenitors to these cells during fetal life. The presence of multiple (MEP) and an increase in the size and characteristics of GATA1 mutant clones in up to 25 % of neonates with the immunophenotypic haematopoietic stem cell (HSC) Down syndrome is consistent with this [9, 11••]; howev- compartment [15••]. HSC and multipotent myeloid pro- er, the reason for their high frequency in Down syndrome genitors in trisomy 21 fetal liver proliferate more in vitro remains unknown (these mutations are not found in compared with normal fetal liver at the same stage of de- normal, disomic cord blood) [9, 11••]. velopment and have increased erythroid-megakaryocyte The vast majority of acquired GATA1 mutations output and gene expression [15••]. Despite the increase (∼97 %) are found in exon 2 and the remainder in exon in megakaryocytes (MK) in trisomy 21 fetal liver, 3.1 of the GATA1 gene, including insertions, deletions MK differentiation is impaired and platelet counts are re- and point mutations [10]. These mutations lead to ex- duced both in fetal blood and in neonates with Down pression of a truncated GATA1s protein [5, 6] and the syndrome suggesting that trisomy 21 itself causes type of GATA1 mutation does not predict which patients dysmegakaryopoiesis [11••, 14, 15••]. with TAM will later progress to ML-DS [10]. Since the The molecular basis for these dramatic changes in fetal GATA1 gene is on the X chromosome, haematopoietic erythro-megakaryopoiesis is not yet clear. Some, but not cells harbouring GATA1 mutations express only GATA1s all, of the features can be recapitulated either in elegant and no longer have the ability to produce the full-length animal models [16–20] or in studies in human embryonic GATA1 protein [5]. The main physiological role of stem cells (ESC) and induced pluripotent stem cells (iPSC) GATA1 is as a regulator of normal megakaryocyte and [21, 22]. Together, these studies have implicated increased erythroid differentiation [24]. How GATA1 transforms expression of various genes on chromosome 21, in trisomy 21 fetal haematopoietic cells is unclear. Forced Curr Hematol Malig Rep Fig. 1 Natural history and pathogenesis of TAM and ML-DS. Schematic of megakaryocyte-erythroid progenitors (MEP) and megakaryocytes. These representation of molecular, biological and clinical data, indicating that cells subsequently acquire N-terminal truncating GATA1 mutations resulting transient abnormal myelopoiesis (TAM) and myeloid leukaemia of Down in TAM in late fetal or early neonatal life. Although most cases of TAM syndrome (ML-DS) are initiated before birth when fetal liver spontaneously and permanently remit (∼90 %) by the age of 6 months, in haematopoietic stem and progenitor cells (HSPC)trisomicfor ∼10 % of cases, additional genetic/epigenetic events lead to further clonal chromosome 21 demonstrate perturbed haematopoiesis with an expansion expansion resulting