| Disease |
Transient abnormal myelopoiesis |
| Note |
Transient abnormal myelopoiesis (TAM) is restricted to newborns with trisomy 21 or those with trisomy 21 mosaicism. The disease is characterized by increased peripheral blood blasts, usually megakaryoblasts, with or without clinical symptoms. Underlying genetics demonstrate somatic mutations in the GATA1 gene. Most cases spontaneously resolve within months without any therapeutic intervention. |
| Phenotype / cell stem origin |
The cell of origin is thought to be the fetal liver hematopoietic stem cell/progenitor cell. |
| Etiology | The current hypothesis is that TAM arises in the liver. Evidence supporting this hypothesis includes the spontaneous resolution of hematopoiesis in the fetal liver within months of birth as hematopoiesis fully switches to the bone marrow, which is similar to the time course of TAM. In addition, severe TAM demonstrates increased blast infiltration of the liver with relative sparing of the bone marrow. Lastly, transgenic mice expressing GATA1 mutations show altered megakaryocyte lineage proliferation/differentiation only in fetal liver progenitors (reviewed in Roy et al., 2009). Evidence demonstrates that the presence of trisomy 21 promotes abnormal megakaryocyte-erythroid proliferation in the fetal liver (Chou et al., 2008; Tunstall-Pedoe et al., 2008). The addition of a somatic GATA1 mutation transforms the progenitors, leading to TAM. The combination of constitutional trisomy 21 with somatic GATA1 mutations has been found to be both necessary and sufficient for TAM (Nikolaev et al., 2013). |
| Epidemiology | As stated previously, TAM is restricted to newborns with trisomy 21, which has an incidence of approximately 1/700 live births. Clinical TAM (i.e. those with obviously increased blasts with or without symptoms) occurs in approximately 4-10% of those with trisomy 21. Approximately 5-16% of those affected with TAM have trisomy 21 mosaicism (Klusmann et al., 2008; Gamis et al., 2011). GATA1 mutations have been identified in 3.8% up to 30% of neonates with Down syndrome (Pine SR et al., 2007; Roberts et al., 2013). In a recent study using targeted next-generation sequencing of all Down syndrome neonates, low abundance GATA1 mutant clones were detected in 20.4% of neonates who were originally negative for mutations by Sanger sequencing/denaturing high performance liquid chromatography and thought to not have TAM (Roberts et al., 2013); the disease associated with these low level GATA1 mutation clones has been termed "silent TAM" due to their indistinguishable clinical picture and laboratory values compared to Down syndrome infants without TAM, including <10% blasts. |
| Clinics | The clinical presentation of TAM is variable, with many infants (10-25%) being asymptomatic, only presenting with increased circulating blasts (Massey et al., 2006; Klusmann et al., 2008). While there is no defined percentage of blasts for the diagnosis of TAM, a threshold of >10% blasts has recently been found to have 100% sensitivity for detecting a coexisting GATA1 mutation, though the specificity is only 74% (Roberts et al., 2013). This specificity is low because, in general, Down syndrome neonates have increased peripheral blood blasts (median 4%; Roberts et al., 2013). Others recommend a blast minimum percentage of 20% (reviewed in Roberts and Izraeli, 2014). Of note, those with "silent TAM" do not have increased blasts compared to Down syndrome neonates without TAM.
The median presentation is within 3-7 days of birth. There is a slight male predominance with a male:female ratio of 1.2-1.5:1 (Massey et al., 2006; Klusmann et al., 2008). Peripheral blood evaluation also usually demonstrates a leukocytosis and an abnormal platelet count (usually thrombocytopenia, but thrombocytosis has also been identified); hemoglobin and absolute neutrophil counts are usually within normal limits. Of note, Down syndrome neonates without a diagnosis of clinical or silent TAM also often have similar peripheral blood abnormalities, so no individual finding other than increased blasts >10% is sensitive for a diagnosis of clinical TAM.
The most common clinical symptom is hepatomegaly, which is a result of megakaryoblast infiltration and/or hepatic fibrosis. This fibrosis is thought to be due to overexpression of platelet-derived growth factor and transforming growth factor-β ( TGFB1)by megakaryoblasts, and portends a poor prognosis (Klusmann et al., 2008). Other clinical findings include splenomegaly, exudative effusions (including pleural, pericardial, and ascites), and respiratory distress (due to hepatomegaly). Clinically severe TAM including these aforementioned symptoms occurs in approximately 10-30% of patients with clinically diagnosed TAM (reviewed in Roberts and Izraeli, 2014). In utero presentations include hydrops fetalis and anemia. |
| Cytology | Blasts are characterized as medium to large cells with high nuclear-to-cytoplasmic ratios, smooth chromatin, prominent nucleoli, and deeply basophilic cytoplasm, often with cytoplasmic blebs. Cytoplasmic azurophilic granules may be identified. |
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| Figure 2: Peripheral blood smear reveals increased blasts which are medium to large in size with smooth chromatin, prominent nucleoli (sometimes multiple) and basophilic cytoplasm. Some of these blasts may demonstrate cytoplasmic blebs. Giant platelets may often be seen. |
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| Pathology | Usually a bone marrow aspirate and/or biopsy does not need to be performed as the peripheral blood blast count is equal to or exceeds the bone marrow blast percentage. If performed, the bone marrow may demonstrate variable numbers of megakaryocytes, including frequent dysplastic forms such as micromegakaryocytes. Variable numbers of blasts may be present, in one study ranging from 0-87%, with a mean of 26% (Massey et al., 2006). Dyserythropoiesis may be seen in up to 25% of patients (Massey et al., 2006). Liver biopsies may demonstrate fibrosis with sinusoidal infiltration by megakaryoblasts (Massey et al., 2006). |
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| Figure 3: Bone marrow biopsy from a patient with TAM demonstrates increased blasts characterized as large cells with round to irregular nuclear contours, prominent nuclei, and mild amounts of cytoplasm. Background maturing erythroid and myeloid precursors are identified. |
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| Other features | Flow cytometry performed on peripheral blood or bone marrow will demonstrate increased blasts expressing CD34, CD117, CD13, CD33, variable CD41, variable CD42b, variable CD61, with aberrant expression of CD7 and CD56, and dim CD4. These blasts may also express CD36, CD71, thrombopoietin receptor (TPO-R) and IL-3 receptor alpha (IL-3Rα) (Klusmann et al., 2008). The blasts are negative for myeloperoxidase (MPO). |
| Cytogenetics | Cytogenetics performed on peripheral blood most often demonstrates only trisomy 21 (Massey et al., 2006). However, approximately 20% of affected infants have additional cytogenetic aberrations including MLL gene rearrangements and complex karyotypes (Klusmann et al., 2008). |
| Genes | TAM is characterized by somatic mutations in the transcription factor gene GATA1 on chromosome Xp11.23. These mutations are predominantly within exon 2 (97%), with the remaining identified mostly in exon 3.1 (Alford et al., 2011). GATA1 mutations result in N-terminal truncating mutations leading to a shortened GATA1 protein, GATA1s. Of note, 10-20% of cases of TAM have multiple GATA1 mutant clones (Alford et al., 2011; Roberts et al., 2013). Whole exome sequencing of TAM cases has reveal low numbers of non-silent mutations in other genes in these patients (1.7, range 1-5; Yoshida et al., 2013). However, Nikolaev et al. (2013) found that the presence of such additional mutations can accumulate in TAM without immediate progression to ML-DS, and that these individuals with additional mutations can still have disease regression. |
| Treatment | Approximately 66-84% of infants will have spontaneous resolution of their blasts and symptoms without a need for intervention (Klusmann et al., 2008; Gamis et al., 2011). The remaining infants may need supportive therapy or chemotherapy. In previous trials, supportive care measures including exchange transfusions and/or leukapheresis were provided for hyperviscosity, blast counts >100K/uL, organomegaly with respiratory compromise, heart failure, hydrops fetalis, liver dysfunction, and disseminated intravascular coagulation (DIC) (Gamis et al., 2011). Even more severe life-threatening symptoms have been treated successfully with cytarabine (cytosine arabinose), to which the blasts are highly sensitive (Massey et al., 2006). |
| Evolution | The majority of patients (66-84%) have spontaneous resolution of clinical and laboratory abnormalities without treatment within 2-3 months (Klusmann et al., 2008). Peripheral blasts usually clear prior to hepatomegaly resolution (Gamis et al., 2011). Approximately 16-30% of infants, whether they were asymptomatic or had clinical symptoms, develop myeloid leukemia of Down syndrome (Klusmann et al., 2008) (see below). |
| Prognosis | While most infants have spontaneous resolution, approximately 15-20% of infants still die; however, approximately half of these deaths are not TAM-related, but instead related to other congenital abnormalities of trisomy 21 (Klusmann et al., 2008; Gamis et al., 2011). TAM mortality risk factors include WBC >100 K/uL, prematurity, ascites, effusions, bleeding diathesis/ coagulopathy, and failure to spontaneously clear peripheral blasts (Klusmann et al., 2008). Those with pathologically diagnosed hepatic fibrosis are more likely to die of disease (Gamis et al., 2011). |
| Disease |
Myeloid leukemia of Down syndrome |
| Note |
Myeloid leukemia of Down syndrome (ML-DS) encompasses a spectrum of myelodysplastic syndrome and its evolution into leukemia in children with Down syndrome. |
| Etiology | Similar to TAM, trisomy 21 and a somatic GATA1 mutation are thought to be required for the development of ML-DS. However, for this progression, additional genetic and/or epigenetic events are required. Children over 5 years old may not have mutations in the GATA1 gene, and possible consideration should be given to a more conventional MDS or AML similar to those diagnosed in non-Down syndrome patients; these children may need therapy with appropriate non-Down syndrome protocols.
In those under 5 years of age, most cases of ML-DS (~70%) are acute megakaryoblastic leukemia (AML M7 by French-American-British (FAB) categorization) (Gamis et al, 2003). Occasional presentations of FAB M0, M1, M2, and M4/M5 have also been reported (Lange et al., 1998; Rao et al., 2006). |
| Epidemiology | The incidence of acute myeloid leukemia in individuals with Down syndrome is 0.5-3%, up to 150 times greater than that in individuals without Down syndrome of the same age; the incidence of acute megakaryoblastic leukemia in individuals with Down syndrome is up to 500 times greater than that in individuals without Down syndrome (Creutzig et al., 1996; Hasle et al., 2000). ML-DS usually presents between 1-4 years of age (median 1.5 years) (Klusmann et al., 2008). This disease develops in approximately 16-30% of children with a clinical history of TAM. However, when taking into account those with "silent TAM", the risk of developing ML-DS is approximately 5-11% (Roberts et al., 2013). At this time, there are no specific clinical, laboratory, or molecular features that predict the risk of TAM transforming into ML-DS. Similarly, whether an individual receives treatment for TAM has not been correlated with the progression to ML-DS.
Of note, GATA1 gene mutation testing/monitoring is not currently the standard of care in patients with Down syndrome. Many groups advocate for a peripheral blood smear with differential at birth and every three months thereafter until the age of 4 years, at which time the risk of leukemia is reduced (Roy et al., 2009; Mateos et al., 2015; Bhatnagar et al., 2016). |
| Clinics | ML-DS may occur after a remission time period from TAM, or as an overt progression/evolution of TAM without a period of remission. In the latter, the infant may have persistent abnormal laboratory values over several months, and in the former, the laboratory values tend to normalize. In those with silent TAM or in remission, ML-DS is usually first detected by thrombocytopenia with or without leukopenia and anemia and with low numbers or absent circulating blasts (Lange et al., 1998). In approximately 70% of patients, myelodysplastic syndrome precedes acute leukemia (Creutzig et al., 1996). Hepatosplenomegaly may be present. Compared to non-Down syndrome cases of myeloid leukemia, ML-DS cases are less likely to have lymphadenopathy and CNS blast involvement (Gamis et al., 2003). |
| Cytology | Peripheral blood and bone marrow blasts in ML-DS are similar to those in TAM, both morphologically and immunophenotypically. The bone marrow aspirate may be hemodilute and/or aparticulate due to marrow fibrosis hampering aspiration. During the myelodysplastic syndrome phase, dysplastic changes of megakaryocytes and erythroid cells may also be identified along with low levels of blasts in the bone marrow. |
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| Figure 4: Increased blasts may be identified on a bone marrow aspirate if it does contain particles. These blasts are characterized as medium to large sized cells with round to irregular nuclear contours, smooth chromatin, prominent nucleoli (sometimes multiple), and basophilic cytoplasm often with cytoplasmic blebs. Rare blasts may demonstrate cytoplasmic granules such as the blast in the bottom center. Dysplastic megakaryocytes may also be identified such as the small megakaryocyte at the top center. |
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| Pathology | A bone marrow biopsy usually demonstrates progressive fibrosis. Blasts and dysplastic megakaryocytes are the predominant cells. The blasts have a similar immunophenotype to those in TAM, expressing CD34, CD117, CD13, CD33, CD36, CD71, variable CD41, variable CD42b, variable CD61, CD56, dim CD4, and aberrant expression of CD7 (Gamis et al., 2003); however, approximately 50% of cases do not express CD34, and 30% of cases do not express CD56 and CD41. |
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| Figure 5: In the bone marrow biopsy obtained from the same patient demonstrated in Figure 4, the core biopsy demonstrates increased blasts with prominent nucleoli in a background of maturing erythroid and myeloid precursors. |
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| Figure 6: Other bone marrow biopsies may demonstrate marked fibrosis, as demonstrated by the bottom panel stained for reticulin. The core biopsy can demonstrate a marked increase in atypical and dysplastic megakaryocytes, many of which are blasts. The inset panel demonstrates CD117 immunohistochemical staining of the megakaryoblasts. |
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| Cytogenetics | Karyotypes in ML-DS often demonstrate only the constitutional trisomy 21 (25-29% of cases) (Lange et al., 1998; Blink et al., 2014). Recurrent genetic abnormalities such as t(8;21), t(15;17), and inv(16) are underrepresented in this cohort compared to those without Down syndrome. The translocation t(1;22) often found in infant megakaryoblastic leukemia is only rarely found in ML-DS. However, trisomy 8 is a common cytogenetic abnormality, occurring in 13-36% of patients, as is an additional nonconstitutional chromosome 21 (Creutzig et al., 1996; Lange et al., 1998; Gamis et al., 2003; Blink et al., 2014). Loss of chromosome 5 and/or loss of chromosome 7 material is present in 23% of cases (Blink et al., 2014). |
| Genes | N-terminal somatic mutations in the GATA1 gene are present in all cases of ML-DS, and, usually, an individual has the same GATA1 clone in both TAM and ML-DS. However, 10-20% of cases of TAM have multiple GATA1 mutant clones, and the larger size of the GATA1 mutant clone has not been found to always correspond with the clone present in ML-DS (Nikolaev et al., 2013; Yoshida et al., 2013). By whole exome sequencing, more non-silent mutations in additional genes are present in ML-DS compared to TAM, with recurrent mutations identified in core cohesion components (including RAD21 and STAG2), CTCF, epigenetic regulators (including EZH2 and KANSL1), RAS pathway genes (including NRAS, JAK1, and JAK2), and other genes (including DCAF7 and TP53) (Yoshida et al., 2013). |
| Treatment | Unlike TAM, ML-DS does require chemotherapy to achieve complete remission (CR). However, compared to non-Down syndrome pediatric acute leukemia, they can be treated with reduced intensity chemotherapy protocols without stem cell transplantation. Reduced chemotherapy intensity is encouraged due to high rates of treatment toxicity in Down syndrome children (Lange et al., 1998). |
| Prognosis | Unlike non-Down syndrome myeloid leukemia, ML-DS has a better prognosis, with better induction remission rates and reduced relapse rates (Lange et al., 1998; Gamis et al., 2003; Rao et al., 2006). Blink et al. (2014) reported a 7-year event-free and overall survival rate of 78% and 79%, respectively. However, ML-DS children are still at high risk for treatment-related deaths, often due to infection (Lange et al., 1998; Rao et al., 2006). White blood count >20K/uL and age >3 years are independent predictors for poor event-free survival (Blink et al., 2014). In another study, age >2 years was correlated with a five fold increase in adverse outcomes (Gamis et al., 2003). A normal karyotype (except for the constitutional trisomy 21) has also been found to independently predict inferior overall survival, event-free survival, and relapse-free survival (Blink et al., 2014). |
| Down syndrome preleukemia and leukemia. |
| Maloney KW, Taub JW, Ravindranath Y, Roberts I, Vyas P |
| Pediatr Clin North Am. 2015 Feb;62(1):121-37 |
| PMID 25435116 |
| |
| A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. |
| Massey GV, Zipursky A, Chang MN, Doyle JJ, Nasim S, Taub JW, Ravindranath Y, Dahl G, Weinstein HJ; Children's Oncology Group (COG). |
| Blood. 2006 Jun 15;107(12):4606-13. |
| PMID 16469874 |
| |
| Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia |
| Alford KA, Reinhardt K, Garnett C, Norton A, Böhmer K, von Neuhoff C, Kolenova A, Marchi E, Klusmann JH, Roberts I, Hasle H, Reinhardt D, Vyas P; International Myeloid Leukemia-Down Syndrome Study Group. |
| Blood. 2011 Aug 25;118(8):2222-38 |
| PMID 21715302 |
| |
| Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. |
| Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I. |
| Curr Hematol Malig Rep. 2016 Oct;11(5):333-41. |
| PMID 27510823 |
| |
| Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. |
| Blink M, Zimmermann M, von Neuhoff C, Reinhardt D, de Haas V, Hasle H, O'Brien MM, Stark B, Tandonnet J, Pession A, Tousovska K, Cheuk DK, Kudo K, Taga T, Rubnitz JE, Haltrich I, Balwierz W, Pieters R, Forestier E, Johansson B, van den Heuvel-Eibrink MM, Zwaan CM. |
| Haematologica. 2014 Feb;99(2):299-307 |
| PMID 23935021 |
| |
| Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. |
| Buitenkamp TD, Izraeli S, Zimmermann M, Forestier E, Heerema NA, van den Heuvel-Eibrink MM, Pieters R, Korbijn CM, Silverman LB, Schmiegelow K, Liang DC, Horibe K, Arico M, Biondi A, Basso G, Rabin KR, Schrappe M, Cario G, Mann G, Morak M, Panzer-Grümayer R, Mondelaers V, Lammens T, Cavé H, Stark B, Ganmore I, Moorman AV, Vora A, Hunger SP, Pui CH, Mullighan CG, Manabe A, Escherich G, Kowalczyk JR, Whitlock JA, Zwaan CM |
| Blood. 2014 Jan 2;123(1):70-7 |
| PMID 24222333 |
| |
| Trisomy 21 enhances human fetal erythro-megakaryocytic development. |
| Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, Brooks JS, Choi JK, Gewirtz AM, Danet-Desnoyers GA, Nemiroff RL, Weiss MJ |
| Blood. 2008 Dec 1;112(12):4503-6 |
| PMID 18812473 |
| |
| Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group. |
| Creutzig U, Ritter J, Vormoor J, Ludwig WD, Niemeyer C, Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J |
| Leukemia. 1996 Nov;10(11):1677-86. |
| PMID 8892666 |
| |
| Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. |
| Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalová K, Stark B, Harrison CJ, Teigler-Schlegel A, Johansson B |
| Blood. 2008 Feb 1;111(3):1575-83 |
| PMID 17971484 |
| |
| Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. |
| Gamis AS, Alonzo TA, Gerbing RB, Hilden JM, Sorrell AD, Sharma M, Loew TW, Arceci RJ, Barnard D, Doyle J, Massey G, Perentesis J, Ravindranath Y, Taub J, Smith FO. |
| Blood. 2011 Dec 22;118(26):6752-9 |
| PMID 21849481 |
| |
| Increased 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. |
| Gamis AS, Woods WG, Alonzo TA, Buxton A, Lange B, Barnard DR, Gold S, Smith FO; Children's Cancer Group Study 2891. |
| J Clin Oncol. 2003 Sep 15;21(18):3415-22 |
| PMID 12885836 |
| |
| Risks of leukaemia and solid tumours in individuals with Down's syndrome |
| Hasle H, Clemmensen IH, Mikkelsen M. |
| Lancet. 2000 Jan 15;355(9199):165-9 |
| PMID 10675114 |
| |
| Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group |
| Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S |
| Blood. 2010 Feb 4;115(5):1006-17 |
| PMID 19965641 |
| |
| Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. |
| Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, Pekrun A, Macakova-Reinhardt K, Reinhardt D. |
| Blood. 2008 Mar 15;111(6):2991-8. |
| PMID 18182574 |
| |
| Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. |
| Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB, Gold S, Sanders J, Neudorf S, Smith FO, Woods WG. |
| Blood. 1998 Jan 15;91(2):608-15. |
| PMID 9427716 |
| |
| Down syndrome and leukemia: insights into leukemogenesis and translational targets. |
| Mateos MK, Barbaric D, Byatt SA, Sutton R, Marshall GM |
| Transl Pediatr. 2015 Apr;4(2):76-92. |
| PMID 26835364 |
| |
| Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. |
| Nikolaev SI, Santoni F, Vannier A, Falconnet E, Giarin E, Basso G, Hoischen A, Veltman JA, Groet J, Nizetic D, Antonarakis SE. |
| Blood. 2013 Jul 25;122(4):554-6 |
| PMID 23733339 |
| |
| Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. |
| Pine SR, Guo Q, Yin C, Jayabose S, Druschel CM, Sandoval C. |
| Blood. 2007 Sep 15;110(6):2128-31 |
| PMID 17576817 |
| |
| Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. |
| Rao A, Hills RK, Stiller C, Gibson BE, de Graaf SS, Hann IM, O'Marcaigh A, Wheatley K, Webb DK |
| Br J Haematol. 2006 Mar;132(5):576-83 |
| PMID 16445830 |
| |
| GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia |
| Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, Vallance G, Perkins K, Marchi E, McGowan S, Roy A, Cowan G, Anthony M, Gupta A, Ho J, Uthaya S, Curley A, Rasiah SV, Watts T, Nicholl R, Bedford-Russell A, Blumberg R, Thomas A, Gibson B, Halsey C, Lee PW, Godambe S, Sweeney C, Bhatnagar N, Goriely A, Campbell P, Vyas P; Oxford-Imperial Down Syndrome Cohort Study Group. |
| Blood. 2013 Dec 5;122(24):3908-17. |
| PMID 24021668 |
| |
| Haematopoietic development and leukaemia in Down syndrome. |
| Roberts I, Izraeli S. |
| Br J Haematol. 2014 Dec;167(5):587-99. |
| PMID 25155832 |
| |
| Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. |
| Roy A, Roberts I, Norton A, Vyas P |
| Br J Haematol. 2009 Oct;147(1):3-12 |
| PMID 19594743 |
| |
| Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations |
| Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A, Vyas P, Roberts I |
| Blood. 2008 Dec 1;112(12):4507-11 |
| PMID 18689547 |
| |
| The landscape of somatic mutations in Down syndrome-related myeloid disorders. |
| Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S. |
| Nat Genet. 2013 Nov;45(11):1293-9 |
| PMID 24056718 |
| |
