- Helen Doolittle, Wellcome Trust/Oxford BRC Clinical Training Fellow
- Jessica Doondeea, Research Associate
- Gaetan Juban, LLR funded post-doctoral fellow
- Dimitris Karamitros, CRUK funded post-doctoral fellow
- I-Jun Lau, Clinical Research Fellow
- Ludovic Llhermitte, Clinican Scientist/Post Doctoral Fellow
- Georg Otto, Post-doc
- Kelly Perkins, LLR funded Post-doc
- Lynn Quek, MRC funded Clinician Scientist/Post-doc
- Marina Samitsch, DPhil Student
- Batchimeg Usukhbayar, Research Associate
- Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M, Aztberger A, Schuh A, Grimwade D, Ivey A, Virgo P, Hills R, McSkeane T, Arrazi J, Knapper S, Brookes C, Davies B, Price A, Wall K, Griffiths M, Cavenagh J, Majeti R, Weissman I, Burnett A, and Vyas P (2012) Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia.
- Della Porta Matteo G, Picone Cristina, Pascutto Cristiana, Malcovati Luca, Tamura Hideto, Handa Hiroshi, Czader Magdalena, Freeman Sylvie, Vyas Paresh, Porwit Anna, Saft Leonie, Westers Theresia M, Alhan Canan, Cali Claudia, van de Loosdrecht Arjan A, and Ogata Kiyoyuki (2012) Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study. Haematologica, 97(8):1209-17.
- Eyre Toby, Schwab Claire J, Kinstrie Ross, McGuire Ann K, Strefford Jen, Peniket Andrew, Mead Adam, Littlewood Tim, Holyoake Tessa L, Copland Mhairi, Moorman Anthony V, Harrison Christine J, and Vyas Paresh (2012) Episomal amplification of NUP214-ABL1 fusion gene in B-cell acute lymphoblastic leukemia. Blood, 120(22):4441-3.
- Goodyear O C, Dennis M, Jilani N Y, Loke J, Siddique S, Ryan G, Nunnick J, Khanum R, Raghavan M, Cook M, Snowden J A, Griffiths M, Russell N, Yin J, Crawley C, Cook G, Vyas P, Moss P, Malladi R, and Craddock C F (2012) Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia. Blood.
- Jan Max, Snyder Thomas M, Corces-Zimmerman M R, Vyas Paresh, Weissman Irving L, Quake Stephen R, and Majeti Ravindra (2012) Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med, 4(149):149ra118.
Our lab studies the stem/progenitor biology in normal haemopoiesis and in myeloid disease, especially Acute Myeloid Leukaemia (AML) in children and adults.
Normal haemopoiesis: Prospective purification and characterization of stem/progenitor cells in normal haemopoiesis and leukemia has led to seminal observations in stem cell and cancer biology. In both human and mouse, multipotent haemopoietic stem cells (HSCs) generate a hierarchy of proliferative progenitor populations that progressively lose lineage potential as they pass through lineage restriction points. Though much progress has been made, there is still much we don't understand about the molecular mechanisms underpinning stem-cell self-renewal and the transition from stem-cell to progenitor compartments.
Acute Myeloid Leukaemia: AML is the commonest form of aggressive leukaemia in adults. AML usually shows initial response to current chemotherapy regimes but then often relapses. Inability to control tumour is the commonest cause of death in AML patients. Relapse occurs from expansion of chemoresistant leukaemic cells. A candidate population of chemoresistant cells are AML leukaemic stem cells (LSCs), which were the first cancer stem cells (CSC) to be described. The cancer stem cell hypothesis postulates that cancers are organised in cellular hierarchies, like normal tissues. At the hierarchy apex are multi-potent, largely quiescent, long-lived CSCs with marked self-renewal capacity that initiate and sustain disease. However, there is debate about how many LSC populations there, the nature of the cellular hierarchy in AML, the relationship between normal stem/progenitor cells and LSCs. Answers to these questions are critical in understanding how oncogenic changes result in transformation.
Adult AML (Drs Goardon, Quek and Marchi, Terri Cornforth and Batchimeg) We have active program in LSC biology (see above).
We have concentrated in purifying and defining the leukaemic stem cell population in AML and studying its molecular and cellular biology. On the basic science we collaborate with Prof Sten-Eirik Jacobsen (WIMM, Oxford) and Prof Tariq Enver (UCL, London). The work has led to novel translational stem cell studies in the UK AML trials group (CI Prof Burnett and Russell), Prof Craddock and Dr Freeman (Birmingham), Prof Grimwade (Kings College London), Dr Campbell (Sanger Centre Cambridge), and collaborative program with the Weissman/Majeti labs in Stanford.
One of our recent findings was to show that in ~80% of human CD34+ Acute Myeloid Leukaemia, two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. Both populations have leukemic stem cell (LSC) activity and are hierarchically ordered, with one LSC population giving rise to the other. Global gene expression profiling and immunophenotype analysis show the LSC populations are molecularly distinct and resemble normal progenitors but not stem cells. The more mature LSC population most closely mirrors normal granulocyte-macrophage progenitors (GMP) and the immature LSC population a previously uncharacterised progenitor functionally similar to murine lymphoid-primed multipotential progenitors (LMPP). Taken together, this suggests that primary CD34+ AML is a progenitor disease where LSCs have acquired abnormal self-renewal potential (Figure 1).
AML in children and infants with Down Syndrome (Drs Juban, Alford, Vallance, Helen Richmond) We have an active program into the basic and applied science of myeloid leukaemia in infants and children with Down Syndrome (DS). This is a collaborative program with Prof Irene Roberts (Imperial College London).
DS is one of the commonest congenital disorders in Western countries, affecting 1/700-1000 live births. Population and cancer registry-based studies show children and neonates with DS have a 10-20-fold increased risk of developing leukaemia, despite not being cancer prone in general. Neonates with DS can present with Transient Abnormal Myelopoeisis (TAM also known as Transient Myeloproliferative Disorder (TMD) or Transient Leukaemia), a clonal myeloid illness of the megakaryocyte/erythroid lineages. ~20-30% of infants with TAM progress to Acute Megakaryocytic Leukaemia (AMKL also known as AML M7 or DS-Myeloid Leukaemia – DS-ML). Overall, children with DS are ~500-fold more likely to develop AMKL. In addition to trisomy 21 (T21), TAM and AMKL cells are also uniquely marked by acquired genomic mutations in the key megakaryocyte-erythroid transcription factor, GATA1.
Our work ranges from studying the haemopoietic defect in TAM and AMKL, understanding the molecular role played by mutant GATA1 protein and finally developing strategies to identify babies at risk of developing AMKL so that we can develop pre-emptive strategies to prevent AML in these babies/infants.
Normal haemopoiesis (Marina Samitch) We have a joint program with the Jacobsen laboratory to understand the cellular and molecular steps that govern the differentiation of human HSC to the earliest progenitor populations. We are using a combination of FACS purification together with in vitro and in vivo assays of cell potential and combining this with molecular analyses of purified populations.
Crystal Structure of GATA1 (Dr Nurmohamed) In collaboration with Dr Porcher and Dr Mancini at the Division of Structural (http://www.strubi.ox.ac.uk/strubi/) we have an integrated program to solve the structure of GATA1 and the GATA1 mutants alone and in complexes with its partners.
For a Word .doc file of all publications by Paresh Vyas, please click here.