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: 4.94). 08/2009; 147(1):3-12. DOI: 10.1111/j.1365-2141.2009.07789.x
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vincristine (VCR) resistance remains a major challenge for the successful treatment of leukemias. MicroRNAs (miRNAs) have a role in proliferation, differentiation and apoptosis, and are associated with poor prognosis phenotypes. Co-expression of miR-125b and miR-99a contribute to VCR resistance to CMK cells due to actively transcribed miR99a/miR-125b locus on chromosome 21q21.1. Here, we show that miR-99a downregulates the targets FKBP51 and IGF1R in CMK cell lines which, in turn, increase p-Akt (Ser473) levels. Our results suggest that these miRNAs can possibly be used in the development of therapies for the treatment of leukemia.
    Hematology/ Oncology and Stem Cell Therapy 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Children with constitutional trisomy 21 (cT21, Down Syndrome, DS) are at a higher risk for both myeloid and B-lymphoid leukaemias. The myeloid leukaemias are often preceded by a transient neonatal pre-leukaemic syndrome, Transient Abnormal Myelopoiesis (TAM). TAM is caused by cooperation between cT21 and acquired somatic N-terminal truncating mutations in the key haematopoietic transcription factor GATA1. These mutations, which are not leukaemogenic in the absence of cT21, are found in almost one-third of neonates with DS. Analysis of primary human fetal liver haematopoietic cells and of human embryonic stem cells demonstrates that cT21 itself substantially alters human fetal haematopoietic development. Consequently, many haematopoietic developmental defects are observed in neonates with DS even in the absence of TAM. Although studies in mouse models have suggested a pathogenic role of deregulated expression of several chromosome 21-encoded genes, their role in human leukaemogenesis remains unclear. As cT21 exists in all embryonic cells, the molecular basis of cT21-associated leukaemias probably reflects a complex interaction between deregulated gene expression in haematopoietic cells and the fetal haematopoietic microenvironment in DS.
    British Journal of Haematology 08/2014; · 4.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: About a quarter of children with Down syndrome and transient abnormal myelopoiesis (TAM) progress to acute megakaryoblastic leukemia (AMKL). We describe isolated dysmegakaryopoiesis despite complete resolution of TAM in an 18-month-old girl, who developed AMKL 6 months later.
    Journal of Pediatric Hematology/Oncology 01/2012; 34(8):640. · 0.96 Impact Factor

Full-text (2 Sources)

Available from
Jan 16, 2015