Publications

• Goardon Nicolas, Marchi Emanuele, Atzberger Ann, Quek Lynn, Schuh Anna, Soneji Shamit, Woll Petter, Mead Adam, Alford Kate A, Rout Raj, Chaudhury Salma, Gilkes Amanda, Knapper Steve, Beldjord Kheira, Begum Suriya, Rose Susan, Geddes Nicola, Griffiths Mike, Standen Graham, Sternberg Alexander, Cavenagh Jamie, Hunter Hannah, Bowen David, Killick Sally, Robinson Lisa, Price Andrew, Macintyre Elizabeth, Virgo Paul, Burnett Alan, Craddock Charles, Enver Tariq, Jacobsen Sten EW, Porcher Catherine, and Vyas Paresh (2011) Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell, 19(1):138-52.

• Vyas Paresh and Jacobsen Sten EW (2011) Clever leukemic stem cells branch out. Cell Stem Cell, 8(3):242-4.

• Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, Pellagatti A, Wainscoat J S, Hellstrom-Lindberg E, Gambacorti-Passerini C, Godfrey A L, Rapado I, Cvejic A, Rance R, McGee C, Ellis P, Mudie L J, Stephens P J, McLaren S, Massie C E, Tarpey P S, Varela I, Nik-Zainal S, Davies H R, Shlien A, Jones D, Raine K, Hinton J, Butler A P, Teague J W, Baxter E J, Score J, Galli A, Della Porta M G, Travaglino E, Groves M, Tauro S, Munshi N C, Anderson K C, El-Naggar A, Fischer A, Mustonen V, Warren A J, Cross N CP, Green A R, Futreal P A, Stratton M R, and Campbell P J (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med, 365(15):1384-95.

• Tehranchi Ramin, Woll Petter S, Anderson Kristina, Buza-Vidas Natalija, Mizukami Takuo, Mead Adam J, Astrand-Grundstrom Ingbritt, Strombeck Bodil, Horvat Andrea, Ferry Helen, Dhanda Rakesh S, Hast Robert, Ryden Tobias, Vyas Paresh, Gohring Gudrun, Schlegelberger Brigitte, Johansson Bertil, Hellstrom-Lindberg Eva, List Alan, Nilsson Lars, and Jacobsen Sten EW (2010) Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med, 363(11):1025-37.

• Tunstall-Pedoe Oliver, Roy Anindita, Karadimitris Anastasios, de la Fuente Josu, Fisk Nicholas M, Bennett Phillip, Norton Alice, Vyas Paresh, and Roberts Irene (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood, 112(12):4507-11.

Background

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.

Projects

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.