Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: A multi-step model of myeloid leukaemogenesis

Department of Haematology, Imperial College London, London, UK.
British Journal of Haematology (Impact Factor: 4.71). 08/2009; 147(1):3-12. DOI: 10.1111/j.1365-2141.2009.07789.x
Source: PubMed


Children with Down syndrome (DS) have a marked increase in susceptibility to Acute Megakaryoblastic Leukaemia (DS-AMKL) and the closely linked neonatal preleukaemic syndrome, Transient Myeloproliferative Disorder (DS-TMD). The distinct stages of DS-TMD and DS-AMKL provide an excellent tractable model to study leukaemogenesis. This review focuses on recent studies describing clinical, haematological and biological features of DS-AMKL and DS-TMD. The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS-AMKL and DS-TMD may be useful in diagnosis and assessing minimal residual disease. These findings raise the possibility of population-based screening strategies for DS-TMD and the development of treatment to eliminate the preleukaemic TMD clone to prevent DS-AMKL. Advances in our understanding of perturbed haemopoiesis in DS, the role of GATA1 and of cooperating mutations are also discussed. These findings have implications for leukaemia biology more broadly given the frequency of acquired trisomy in other human leukaemias.

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Available from: Alice Norton, Jan 16, 2015
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    • "Independent confirmation has however not yet been reported. A more detailed review of GATA1 and its leukaemogenic role in DS is beyond the scope of this report and the reader is referred to several focused reviews of this gene (Vyas & Crispino, 2007; Malinge et al, 2009; Roy et al, 2009). "
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    ABSTRACT: Children with trisomy 21 have a unique predisposition to develop a megakaryoblastic proliferative disease of varying severity during their first 3 months of life. This disorder exists in no other children or adults without the presence of trisomy 21 and only occurs in the fetal or neonatal period of life. Its spontaneous resolution in most cases further delineates it from otherwise indistinguishable neonatal leukaemias. The identification that GATA1 mutations are the leukaemogenic source along with three recently reported prospective clinical trials now provide a clearer understanding of this haematopoietic disorder. These recent advances in this enigmatic disorder, now known as Transient Myeloproliferative Disorder, are reviewed here in order to bring clarity to the breadth of organ involvement, the range of severity, the risk factors for mortality, the therapeutic options for severe manifestations, the natural course of spontaneous resolution regardless of therapy, and the elucidation of the subsequent risk for myeloid leukaemia.
    Full-text · Article · Sep 2012 · British Journal of Haematology
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    • "Histological evaluation of the bone marrow confirmed the megakaryocyte hyperplasia as has been reported in Ts65Dn mice and in DS patients [2], [33], as well as a significant and normal age-related decrease in bone mass in Ts65Dn mice. This is particularly interesting given that DS patients have a life expectancy well into the 5th decade of life and are presenting in increasing numbers with low bone mass and fracture [34]. "
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    ABSTRACT: Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population.
    Full-text · Article · Aug 2012 · PLoS ONE
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    • "Transient myeloproliferative disorder (TMD) of Down syndrome (DS), also known as transient abnormal myelopoiesis, characteristically manifests in the first few days of life with numerous circulating blast cells exceeding the number of blast cells in the bone marrow and with spontaneous or no resolution within a few weeks [1-3]. Occasionally, however, TMD has preceded acute megakaryoblastic leukemia (AML-M7) after a period of remission lasting several months to years [4-6]. Tumor lysis syndrome (TLS) is rarely reported after initiation of effective chemotherapy as a complication of transient myeloproliferative disorder [7]. "
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    ABSTRACT: Transient myeloproliferative disorder is a hematologic abnormality characterized by an uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow that primarily affects newborns and babies with Down syndrome. Tumor lysis syndrome is rarely associated with transient myeloproliferative disorder. Transient myeloproliferative disorder was diagnosed in a seven-day-old baby girl with Down syndrome, who was referred to our department due to hyperleukocytosis. Our patient developed tumor lysis syndrome, successfully treated with rasburicase, as a complication of transient myeloproliferative disorder resulting from rapid degradation of myeloid blasts after initiation of effective chemotherapy. Tumor lysis syndrome is rarely reported as a complication of transient myeloproliferative disorder. To the best of our knowledge, this is the first case of a newborn with Down syndrome and transient myeloproliferative disorder treated with rasburicase for developing tumor lysis syndrome.
    Full-text · Article · Aug 2011 · Journal of Medical Case Reports
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