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Bone Marrow Failure & MDS

Genomics

Team Leads

Dr Alex Smith
Staff Scientist
E-mail: alexander.a.smith@kcl.ac.uk  
Tel: +44(0)207 848 5808

Dr Azim Mohamedali
Staff Scientist
E-mail: azim.mohamedali@kcl.ac.uk
Tel: +44(0)207 848 5835 

Research Focus:

The Bone Marrow Failure (BMF) Genomics Unit aims to unravel the unique landscape of mutations that characterise the different bone marrow failure syndromes as well as understanding the molecular evolution from normal to malignant haematopoiesis. Through a range of state-of-the art genomic techniques we focus on:

  • Delineation of the mechanisms that propagate chromosomal instability in myeloid malignancies.
  • Differential gene expression across bone marrow failure syndromes.
  • Identification of microRNA target genes on 5q- and chromosome 7 MDS subtypes using a novel functional assay.
  • Clonal evolution and engraftment kinetics of patient bone marrow stem cells in xenografted mice through whole-exome sequencing/targeted sequencing.
  • Mutational landscape in the different MDS bone marrow compartments such as hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), granulocyte macrophage progenitors (GMPs) and megakaryocyte erythrocyte progenitors (MEPs).

Funding:

  • Leukaemia and Lymphoma Research Programme Grant 10024 for 4 years: Immunedysregulation in bone marrow failure syndromes: Implications for pathogenesis and clonal evolution. Awarded 20 July 2010.
  • Project for a national aplastic anaemia registry and a study of the genetics of the overlap between aplastic anaemia and myelodysplastic syndrome. Funding awarded from Genzyme Therapeutics and Aplastic Anaemia Trust in 2010.
  • A prospective comparison of HLA epitope-matched with standard HLA-matched platelet transfusions in raising the platelet count increment in alloimmunised thrombocytopenic patients with aplastic anaemia or myelodysplastic syndrome – a cross-over superiority trial. Collaborative study with NHS Blood Transfusion. Frunding from NHS Blood and Transplant National Research Review Committee: funding awarded November 2009.
  • Leukaemia and Lymphoma Research. Identification of the target genes of microRNAs (miRNAs) localized to the commonly deleted region on 5q in Myelodysplastic syndromes (MDS) by a novel functional assay.
  • Celgene International Sarl. Can blood be used as surrogate for bone marrow in the detection of neoplastic haempoietic clones?

Patents:

  • WO9960135   Generation of multiple gene products from chimeric fusion proteins by cleavage with ubiquitous endoproteases.
  • WO2008122770 Nucleic acids and libraries.

Selected Publications:

  1. Mohamedali AM, Alkhatabi H, Kulasekararaj A, Shinde S, Mian S, Malik F, Smith AE, Gäken J, Mufti GJ. Utility of peripheral blood for cytogenetic and mutation analysis in myelodysplastic syndrome. Blood. 2013 Jul 25;122(4):567-70.
  2. Gaymes TJ, Mohamedali AM, Patterson M, Matto N, Smith A, Kulasekararaj A, Chelliah R, Curtin N, Farzaneh F, Shall S, Mufti GJ. Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. Haematologica. 2013 Sep;98(9):1397-406.
  3.  Mian SA, Smith AE, Kulasekararaj AG, Kizilors A, Mohamedali AM, Lea NC, Mitsopoulos K, Ford K, Nasser E, Seidl T, Mufti GJ. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome. Haematologica. 2013 Jul;98(7):1058-66.
  4. Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, Gäken J, Pennaneach C, Ireland R, Czepulkowski B, Pomplun S, Marsh JC, Mufti GJ. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol. 2013 Mar;160(5):660-72
  5. Gäken J, Mohamedali AM, Jiang J, Malik F, Stangl D, Smith AE, Chronis C, Kulasekararaj AG, Thomas NS, Farzaneh F, Tavassoli M, Mufti GJ. A functional assay for microRNA target identification and validation. Nucleic Acids Res. 2012  May;40(10):e75.
  6. Jiang J, Cole D, Westwood N, Macpherson L, Farzaneh F, Mufti G, Tavassoli M, Gäken J. Crucial roles for protein kinase C isoforms in tumor-specific killing by apoptin. Cancer Res. 2010 Sep 15;70(18):7242-52.
  7. Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gäken J, Lea NC, Przychodzen  B, Mian SA, Nasser EE, Shooter C, Westwood NB, Strupp C, Gattermann N,  Maciejewski JP, Germing U, Mufti GJ. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood. 2010 Nov 11;116(19):3923-32.
  8. Mohamedali AM, Smith AE, Gaken J, Lea NC, Mian SA, Westwood NB, Strupp C, Gattermann N, Germing U, Mufti GJ. Novel TET2 mutations associated with UPD4q24 in myelodysplastic syndrome. J Clin Oncol. 2009 Aug 20;27(24):4002-6.
  9. Mohamedali A, Gäken J, Twine NA, Ingram W, Westwood N, Lea NC, Hayden J, Donaldson N, Aul C, Gattermann N, Giagounidis A, Germing U, List AF, Mufti GJ. Prevalence and prognostic significance of allelic imbalance by single-nucleotide  polymorphism analysis in low-risk myelodysplastic syndromes. Blood. 2007 Nov 1;110(9):3365-73.

 

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