Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloproliferative Neoplasias

Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target

Leukemia volume 27, pages 1996–2005 (2013)Cite this article

Subjects

Abstract

The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34+ progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Cortes J, Kantarjian H . How I treat newly diagnosed chronic phase CML. Blood 2012; 120: 1390–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hehlmann R . How I treat CML blast crisis. Blood 2012; 120: 737–747.

    Article  CAS  PubMed  Google Scholar 

  3. Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia (vol 23, pg 1054, 2009). Leukemia 2010; 24: 1102–1102.

    Article  Google Scholar 

  4. Perrotti D, Jamieson C, Goldman J, Skorski T . Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest 2010; 120: 2254–2264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Quintas-Cardama A, Cortes J . Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 2009; 113: 1619–1630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Milojkovic D, Apperley JF, Gerrard G, Ibrahim AR, Szydlo R, Bua M et al. Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients. Blood 2012; 119: 1838–1843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Karvela M, Helgason GV, Holyoake TL . Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Expert Rev Anticancer Ther 2012; 12: 381–392.

    Article  CAS  PubMed  Google Scholar 

  8. Hantschel O, Rix U, Superti-Furga G . Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 2008; 49: 615–619.

    Article  CAS  PubMed  Google Scholar 

  9. Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA . Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther 2008; 7: 3169–3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Traer E, MacKenzie R, Snead J, Agarwal A, Eiring AM, O'Hare T et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia 2012; 26: 1140–1143.

    Article  CAS  PubMed  Google Scholar 

  11. Sanchez-Garcia I, Grutz G . Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc Natl Acad Sci USA 1995; 92: 5287–5291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Amarante-Mendes GP, McGahon AJ, Nishioka WK, Afar DEH, Witte ON, Green DR . Bcl-2-independent Bcr-Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-x(L). Oncogene 1998; 16: 1383–1390.

    Article  CAS  PubMed  Google Scholar 

  13. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I et al. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-(XL). J Exp Med 2000; 191: 977–984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood 2005; 105: 3303–3311.

    Article  CAS  PubMed  Google Scholar 

  15. Soliera AR, Mariani SA, Audia A, Lidonnici MR, Addya S, Ferrari-Amorotti G et al. Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1. Leukemia 2012; 26: 1555–1563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allan EK, Holyoake TL, Craig AR, Jorgensen HG . Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia 2011; 25: 985–994.

    Article  CAS  PubMed  Google Scholar 

  17. Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S . Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia 2009; 23: 1446–1454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gonzalez-Herrero I, Vicente-Duenas C, Orfao A, Flores T, Jimenez R, Cobaleda C et al. Bcl2 is not required for the development and maintenance of leukemia stem cells in mice. Carcinogenesis 2010; 31: 1292–1297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 2005; 307: 1101–1104.

    Article  CAS  PubMed  Google Scholar 

  20. Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A et al. ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol 2008; 140: 181–190.

    CAS  PubMed  Google Scholar 

  21. High LM, Szymanska B, Wilczynska-Kalak U, Barber N, O'Brien R, Khaw SL et al. The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs. Mol Pharmacol 2010; 77: 483–494.

    Article  CAS  PubMed  Google Scholar 

  22. Harb JG, Chyla BI, Huettner CS . Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis. Blood 2008; 111: 3760–3769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mak DH, Wang RY, Schober WD, Konopleva M, Cortes J, Kantarjian H et al. Activation of apoptosis signaling eliminates CD34(+) progenitor cells in blast crisis CML independent of response to tyrosine kinase inhibitors. Leukemia 2012; 26: 788–794.

    Article  CAS  PubMed  Google Scholar 

  24. Milojkovic D, Apperley J . Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 2009; 15: 7519–7527.

    Article  CAS  PubMed  Google Scholar 

  25. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68: 3421–3428.

    Article  CAS  PubMed  Google Scholar 

  26. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DCS et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl(+) leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 2006; 103: 14907–14912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Salomoni P, Condorelli F, Sweeney SM, Calabretta B . Versatility of BCR/ABL-expressing leukemic cells in circumventing proapoptotic BAD effects. Blood 2000; 96: 676–684.

    CAS  PubMed  Google Scholar 

  28. Neshat MS, Raitano AB, Wang HG, Reed JC, Sawyers CL . The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: Roles for phosphatidylinositol 3-kinase and Raf. Mol Cell Biol 2000; 20: 1179–1186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Danial NN . BAD: undertaker by night, candyman by day. Oncogene 2008; 27: S53–S70.

    Article  CAS  PubMed  Google Scholar 

  30. Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST . Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 2003; 63: 5716–5722.

    CAS  PubMed  Google Scholar 

  31. Skorski T, Bellacosa A, NieborowskaSkorska M, Majewski M, Martinez R, Choi JK et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997; 16: 6151–6161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bhagwat SV, Crew AP . Novel inhibitors of mTORC1 and mTORC2. Curr Opin Investig Drugs 2010; 11: 638–645.

    CAS  PubMed  Google Scholar 

  33. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. Plos Biol 2009; 7: 371–383.

    Article  CAS  Google Scholar 

  34. Carayol N, Vakana E, Sassano A, Kaur S, Goussetis DJ, Glaser H et al. Critical roles for mTORC2-and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci USA 2010; 107: 12469–12474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010; 16: 205–U115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Koschmieder S, Gottgens B, Zhang P, Iwasaki-Arai J, Akashi K, Kutok JL et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood 2005; 105: 324–334.

    Article  CAS  PubMed  Google Scholar 

  37. Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A et al. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol 2002; 22: 2255–2266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huettner CS, Zhang P, Van Etten RA, Tenen DG . Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000; 24: 57–60.

    Article  CAS  PubMed  Google Scholar 

  39. Radomska HS, Gonzalez DA, Okuno Y, Iwasaki H, Nagy A, Akashi K et al. Transgenic targeting with regulatory elements of the human CD34 gene. Blood 2002; 100: 4410–4419.

    Article  CAS  PubMed  Google Scholar 

  40. Wagner KU, Claudio E, Rucker EB, Riedlinger G, Broussard C, Schwartzberg PL et al. Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly. Development 2000; 127: 4949–4958.

    CAS  PubMed  Google Scholar 

  41. Mihara K, Imai C, Coustan-Smith E, Dome JS, Dominici M, Vanin E et al. Development and functional characterization of human bone marrow mesenchymal cells immortalized by enforced expression of telomerase. Br J Haematol 2003; 120: 846–849.

    Article  CAS  PubMed  Google Scholar 

  42. Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM et al. Modulation of prostate cancer genetic risk by ornega-3 and ornega-6 fatty acids. J Clin Invest 2007; 117: 1866–1875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K et al. BCR-ABL suppresses C/EBP alpha expression through inhibitory action of hnRNP E2. Nat Genet 2002; 30: 48–58.

    Article  CAS  PubMed  Google Scholar 

  44. Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A et al. A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood 2006; 107: 2507–2516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chiang CW, Harris G, Ellig C, Masters SC, Subramanian R, Shenolikar S et al. Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 2001; 97: 1289–1297.

    Article  CAS  PubMed  Google Scholar 

  46. Cirinna M, Trotta R, Salomoni P, Kossev P, Wasik M, Perrotti D et al. Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation. Blood 2000; 96: 3915–3921.

    CAS  PubMed  Google Scholar 

  47. Fang XJ, Yu SX, Eder A, Mao ML, Bast RC, Boyd D et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 1999; 18: 6635–6640.

    Article  CAS  PubMed  Google Scholar 

  48. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107: 4532–4539.

    Article  CAS  PubMed  Google Scholar 

  49. Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    Article  CAS  PubMed  Google Scholar 

  50. Eiring AM, Neviani P, Santhanam R, Oaks JJ, Chang JS, Notari M et al. Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis. Blood 2008; 111: 816–828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Calabretta B, Perrotti D . The biology of CML blast crisis. Blood 2004; 103: 4010–4022.

    Article  CAS  PubMed  Google Scholar 

  52. Jaiswal S, Traver D, Miyamoto T, Akashi K, Lagasse E, Weissman IL . Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci USA 2003; 100: 10002–10007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ravandi FM, Kantarjian HM, Talpaz M, O'Brien S, Faderl S, Giles FJ et al. Expression of apoptosis proteins in chronic myelogenous leukemia. Cancer 2001; 91: 9.

    Article  Google Scholar 

  54. Evangelisti C, Ricci F, Tazzari P, Tabellini G, Battistelli M, Falcieri E et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia 2011; 25: 781–791.

    Article  CAS  PubMed  Google Scholar 

  55. Spender LC, Inman GJ . Phosphoinositide 3-kinase/AKT/mTORC1/2 Signaling Determines Sensitivity of Burkitt's Lymphoma Cells to BH3 mimetics. Mol Cancer Res 2012; 10: 347–359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Airiau K, Mahon F-X, Josselin M, Jeanneteau M, Turcq B, Belloc F . ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib. Exp Hematol 2012; 40: 367–378.

    Article  CAS  PubMed  Google Scholar 

  57. Merino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C et al. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 2012; 119: 5807–5816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zeng Z, Shi YX, Tsao T, Qiu Y, Kornblau SM, Baggerly KA et al. Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. Blood 2012; 120: 2679–2689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvalo PP, Kitada S et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375–388.

    Article  CAS  PubMed  Google Scholar 

  60. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

DP is a Scholar of The Leukemia and Lymphoma Society. This work was supported, in part, by NIH Grants CA095512 and CA163800 (DP), CA16058 (OSU-CCC); Fonds de Recherche Quebec Sante—TheCell (DCR); Lauri Strauss Leukemia and BloodCenter Research Foundations (CSH); the Danish Medical Research Council, the Danish Cancer Society and the Karen Elise Jensen Foundation (PH) grants. JGH was supported, in part, by NIH training Grant HL-07209. We thank L. Hennighausen (NIH, Bethesda, MD, USA) for providing Bcl-x f/f mice; H. Albertz and C. Reinbold (FACS Core Facility, Blood Research Institute, Milwaukee, WI, USA) for technical assistance; J. Perrin (OSU Medical Center, Columbus, OH, USA) for helping in procuring CML specimens andS. Lee (OSU Medical Center, Columbus, OH, USA) for editorial assistance.

Author information

Authors and Affiliations

  1. Department Molecular Virology Immunology and Medical Genetics, Human Cancer Genetics Program, Columbus, OH, USA

    J G Harb, P Neviani, J J Ellis, G J Ferenchak, J J Oaks, C J Walker, M A Caligiuri, G Marcucci & D Perrotti

  2. Blood Center of Wisconsin, Blood Research Institute, Milwaukee, WI, USA

    J G Harb, B J Chyla & C S Huettner

  3. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    P Neviani, M A Caligiuri, G Marcucci & D Perrotti

  4. Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

    P Hokland

  5. Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital and University of Montreal, Montreal, Quebec, Canada

    D C Roy

  6. Department of Internal Medicine, Columbus, OH, USA

    M A Caligiuri & G Marcucci

  7. Dana Farber Cancer Institute, Harvard Medical School, Boston, MA

    C S Huettner

Authors
  1. J G Harb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Neviani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B J Chyla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J J Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G J Ferenchak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J J Oaks
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C J Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Hokland
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D C Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M A Caligiuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Marcucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C S Huettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Perrotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Perrotti.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author contributions

JGH designed, performed experiments and drafted the manuscript; PN, BJC, JJE, CJW, JJO and GJF performed the experiments; GM, PH and DCR provided the patient specimens; MAC and GM provided vital instrumentation and reagents; CSH designed the mouse study; and DP supervised the work and wrote the manuscript. All authors contributed to and approved the final manuscript.

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harb, J., Neviani, P., Chyla, B. et al. Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target. Leukemia 27, 1996–2005 (2013). https://doi.org/10.1038/leu.2013.151

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.151

Keywords

This article is cited by

Search

Advanced search

Quick links