Bone Marrow Characterisation – MDSBio

MDSBio is a national resource that was setup to help the research community study myeloid disorders by banking blood and bone marrow samples taken from patients in hospitals across the UK.  Samples are collected from patients suspected of acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD).

MDSBio aims to benefit patients in the NHS by (i) discovering mechanisms that lead to patients developing these diseases; (ii) to identify ways in which to use existing therapies better; (iii) to identify new therapies for these diseases; (iv) to understand the natural history of these diseases. The resource has already contributed to several new discoveries about these diseases. These discoveries include: 

1. Identification of acquired genetic changes (mutations) that are required in these diseases. This will improve diagnosis and refine our ability to give more accurate prognosis.

2. Identification of disease-propagating cell populations in these diseases. This is important as we can now begin to work out which cells have to be eradicated to cure the disease. 

3. Identification of new more accurate cellular and molecular methods to quantify how much disease is left after treatment. This will help us to use current treatments more effectively. 

4. Finally, the group have worked with a group in Stanford to develop a new therapy for AML. 

Resource Details

  • Longitudinal study established in 2009 with over 50 collaborating centres. 
  • Samples collected from patients aged over 18, with an abnormal blood count requiring investigation by blood and bone marrow, or known to have a blood disorder requiring bone marrow biopsy, or under follow-up with an established diagnosis of MDS/CMML, and from those having an elective orthopaedic surgery who have a normal blood count (control sample). 
  • Currently collecting 1500-2000 samples annually (78 hospitals).
  • Sample types of blood / bone marrow / mononuclear cell fraction.
  • Core demographic and clinical data including follow-up.

Industrial Collaborations

The data collection element of the study allows the focusing of early phase clinical trials to NHS Trusts that are particularly committed to MDS/AML research. This ability to identify populations for study using investigational agents has led to open negotiations with a number of pharmaceutical companies, which are currently ongoing.

Publications 

1.       Gerstung M, Pellagatti A, Malcovati L, Giagounidis A, Porta MG, Jädersten M, Dolatshad H, Verma A, Cross NC, Vyas P, Killick S, Hellström-Lindberg E, Cazzola M, Papaemmanuil E, Campbell PJ, Boultwood J. 2015 Combining gene mutations with gene expression data imrpoves outcome prediction in myelodysplastic syndromes. Nat Commun. 6: Article number: 5901.

2.       Bradbury C, Houlton AE, Akiki S, Gregg R, Rindl M, Khan J, Ward J, Khan N, Griffiths M, Nagra S, Hills R, Burnett A, Russell N, Vyas P, Grimwade D, Craddock C, Freeman SD. Prognostic value of monitoring a candidate immunophenotypic leukemic stem/progenitor cell population in patients allografted for acute myeloid leukemia. Leukemia. 29 p988-91. (2014) PMID:25425198.

3.       Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, Bolli N, Behjati S, Tarpey PS, Nangalia J, Massie CE, Butler AP, Teague JW, Vassiliou GS, Green AR, Du MQ, Unnikrishnan A, Pimanda JE, Teh BT, Munshi N, Greaves M, Vyas P, El-Naggar AK, Santarius T, Collins VP, Grundy R, Taylor JA, Hayes DN, Malkin D; ICGC Breast Cancer Group; ICGC Chronic Myeloid Disorders Group; ICGC Prostate Cancer Group, Foster CS, Warren AY, Whitaker HC, Brewer D, Eeles R, Cooper C, Neal D, Visakorpi T, Isaacs WB, Bova GS, Flanagan AM, Futreal PA, Lynch AG, Chinnery PF, McDermott U, Stratton MR, Campbell PJ. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. Oct 1;3. doi: 10.7554/eLife.02935 (2014). PMID:25271376.

4.       Woll PS, Kjällquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, Erlandsson R, Ngara M, Anderson K, Deng Q, Mead AJ, Stenson L, Giustacchini A, Duarte S, Giannoulatou E, Taylor S, Karimi M, Scharenberg C, Mortera-Blanco T, Macaulay IC, Clark SA, Dybedal I, Josefsen D, Fenaux P, Hokland P, Holm MS, Cazzola M, Malcovati L, Tauro S, Bowen D, Boultwood J, Pellagatti A, Pimanda JE, Unnikrishnan A, Vyas P, Göhring G, Schlegelberger B, Tobiasson M, Kvalheim G, Constantinescu SN, Nerlov C, Nilsson L, Campbell PJ, Sandberg R, Papaemmanuil E, Hellström-Lindberg E, Linnarsson S, Jacobsen SE. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 25 p794-808 (2014)

5.       Papaemmanui E, Gerstung M Malcovati L, Tauro S, Gundem G, Van Loo P, Ellis P, Pellagatti A, Shlien A, Groves M, Forbes SA, Raine K, O’Meara S, Mudie LJ, Hardy C, Latimer C, Hinton J, Jones DR, Butler AP, Teague JW, Galli A, Della Porta MG, Ambaglio I, Quek L, Sternberg A, Walldin G, Gambacorti-Passerini C, Cross N, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122: p 3616-27 2013.

6.       Craddock C, Goardon N, Quek L, Freeman S, Siddique S, Raghavan M, Schuh A, Grimwade D, Virgo P, Hills R, McSkeane T, Arrazi J, Gilkes A, Knapper, Adam Ivey, Brookes C, Miles O, Davies B, Chaudhury S, Pollard T, Price A, Atzberger A, Wall K, Kaur H, Griffiths M, Cavenagh, Majeti R, Weissman I, Burnett A, Vyas P. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukaemia 27:p1028-36 (2013).

7.       Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR and Majeti R. Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia. Science Translational Medicine 29 p149ra118 (2012).

8.       Goodyear O, Dennis M, Loke J, Jilani N, Siddique S, Ryan G, J Nunnick, Khanum R, Raghavan M, Cook M, Snowden J, Griffiths M, Russell N, Yin J, Crawley C, Cook G, Vyas P, Moss P, Malladi R, Craddock C. Azacitidine Induces Expansion of Regulatory T Cells and Induces a Tumor Antigen Specific Response after Allogeneic Stem Cell Transplantation in patients with AML. Blood. 119: p3361-9. (2012).

9.       Frisan, E, Vandekerckhove J, de Thonel A, Pierre-Eugène C, Sternberg A, Gyan E, Dreyfus F, Gabet A, Courtois G, Vyas P, Ribeil Zermati Y, Lacombe C, Mayeux P, Solary E, Garrido C, Hermine O, and Fontenay. M Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes. Blood 119: p1532-42 (2012).

10.   Papaemmanuil E, Cvejic A, Cazzola M, Vyas P, Bowen D, Boultwood J, Wainscoat J, Hellstrom-Lindberg E, Gambacorti-Passerini C, Godfrey A, Rapado I, Rance R, Mudie L, Stephens P, McLaren S, Varela I, Nik-Zainal S, Davies H, Shlien A, Jones D, Raine K, Hinton J, Butler A, Teague JW, Baxter EJ, Score J, Malcovati L, Galli A, Tauro S, Ouwehand W, Stemple D, Fischer A, Mustonen V; Cross N; Green AR, Futreal A, Stratton MF, Campbell PJ. Somatic mutation of SF3B1 in myelodysplasia with ringed sideroblasts and other cancers. NEJM 365: p.1384-95 (2011).

11.   Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Woll P, Mead A, Alford KA, Rout R, Chaudhury S, Gilkes A, Knapper S, Soneji S, Beldjord K, Begum S, Rose S, Geddes N, Griffiths M, Standen G, Sternberg A, Cavenagh J, Hunter H, Bowen D, Killick S, Robinson L, Price A, Macintyre E, Virgo P, Burnett A, Craddock C, Enver T, Jacobsen SEW, Porcher C and Vyas P. Co-existence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia. Cancer Cell 19 p138-52 (2011). 

12.   Tehranchi R, Anderson K, Buza-Vidas N, Åstrand-Grundström I, Strömbeck B, Hast R, Johansson B, Göhring, G, Schlegelberger, B, Rydén T, Vyas P, Singh R, Hellström-Lindberg E, List A, Nilsson L, and Jacobsen SE. Persistance malignant stem cells in del(5q) myelodysplasia in remission. NEJM 363 p1025-37 (2010).

Contact

MDSBio is a National Cancer Reserch Network badged study and is registered on the UK Clinical Research Network Study Portfolio. For more information about the study and to contact a member of the team regarding access, email mds@imm.ox.ac.ukThe resource is directed by Dr. Alexander Sternberg and Prof. Paresh Vyas