Advertisement

Hox Genes pp 349-370 | Cite as

Rational Drug Repurposing Using sscMap Analysis in a HOX-TALE Model of Leukemia

  • Laura M. J. Kettyle
  • Fabio G. Liberante
  • Alexander ThompsonEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1196)

Abstract

Drug discovery and development are often hampered by lack of target identification and clinical tractability. Repurposing of approved drugs to life-threatening diseases such as leukemia is emerging as a promising alternative approach. Connectivity mapping systems link approved drugs with disease-related gene signatures. Relevant preclinical models provide essential tools for system validation and proof-of-concept studies. Herein we describe procedures aimed at generating disease-based gene signatures and applying them to established cross-referencing databases of potential candidate drugs. As a proof of principle, we present the identification of Entinostat as a candidate drug for the treatment of HOX-TALE-related leukemia.

Key words

HOXA9 Meis1 Data mining Gene expression profiles Connectivity mapping (sscMap) Leukemia Entinostat Preclinical model 

Notes

Acknowledgements

The authors would like to thank the staff within the Biological Resource Unit and Bioinformatics Cores, Queen’s University Belfast. Alex Thompson is a recipient of the American Cancer Society for Beginning Investigator Fellowship from the UICC. This work was supported by grants from Leukemia Lymphoma Research, UK (07016 and 09035), the Leukaemia Lymphoma Northern Ireland (LLNI), and Biotechnology and Biological Science Research Council (BBSRC).

References

  1. 1.
    Dickson GJ, Kwasniewska A, Mills KI et al (2009) Hoxa6 potentiates short-term hemopoietic cell proliferation and extended self-renewal. Exp Hematol 37:322–333 e3. doi: 10.1016/j.exphem.2008.10.015, S0301-472X(08)00508-0 [pii]PubMedCrossRefGoogle Scholar
  2. 2.
    Bryder D, Rossi DJ, Weissman IL (2006) Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol 169:338–346. doi: 10.2353/ajpath.2006.060312, S0002-9440(10)62717-4 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Wong P, Iwasaki M, Somervaille TC et al (2007) Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev 21:2762–2774. doi: 10.1101/gad.1602107, gad.1602107 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Lawrence HJ, Sauvageau G, Humphries RK, Largman C (1996) The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells 14:281–291. doi: 10.1002/stem.140281 PubMedCrossRefGoogle Scholar
  5. 5.
    Calvo KR, Sykes DB, Pasillas M, Kamps MP (2000) Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression. Mol Cell Biol 20:3274–85PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Owens BM, Hawley RG (2002) HOX and non-HOX homeobox genes in leukemic hematopoiesis. Stem Cells 20:364–379. doi: 10.1634/stemcells.20-5-364 PubMedCrossRefGoogle Scholar
  7. 7.
    Khan SN, Jankowska AM, Mahfouz R et al (2013) Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia 27:1301–9. doi: 10.1038/leu.2013.80 PubMedCrossRefGoogle Scholar
  8. 8.
    Argiropoulos B, Humphries RK (2007) Hox genes in hematopoiesis and leukemogenesis. Oncogene 26:6766–6776. doi: 10.1038/sj.onc.1210760, 1210760 [pii]PubMedCrossRefGoogle Scholar
  9. 9.
    Golub TR, Slonim DK, Tamayo P et al (1999) Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286:531–537, 7911 [pii]PubMedCrossRefGoogle Scholar
  10. 10.
    Lawrence HJ, Rozenfeld S, Cruz C et al (1999) Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13:1993–1999PubMedCrossRefGoogle Scholar
  11. 11.
    Soulier J, Clappier E, Cayuela JM et al (2005) HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 106:274–286. doi: 10.1182/blood-2004-10-3900, 2004-10-3900 [pii]PubMedCrossRefGoogle Scholar
  12. 12.
    Armstrong SA, Staunton JE, Silverman LB et al (2002) MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30:41–47. doi: 10.1038/ng765 ng765 [pii] PubMedCrossRefGoogle Scholar
  13. 13.
    Ferrando AA, Armstrong SA, Neuberg DS et al (2003) Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 102:262–268. doi:  10.1182/blood-2002-10-3221 2002-10-3221 [pii] PubMedCrossRefGoogle Scholar
  14. 14.
    So CW, Karsunky H, Wong P et al (2004) Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9. Blood 103:3192–3199. doi: 10.1182/blood-2003-10-3722 2003-10-3722 [pii] PubMedCrossRefGoogle Scholar
  15. 15.
    Somervaille TC, Matheny CJ, Spencer GJ et al (2009) Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 4:129–140. doi: 10.1016/j.stem.2008.11.015, S1934-5909(08)00617-6 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Haferlach T, Bacher U, Kohlmann A, Haferlach C (2009) Discussion of the applicability of microarrays: profiling of leukemias. Methods Mol Biol 509:15–33. doi: 10.1007/978-1-59745-372-1_2 PubMedCrossRefGoogle Scholar
  17. 17.
    Wouters BJ, Lowenberg B, Delwel R (2009) A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects. Blood 113:291–298. doi: 10.1182/blood-2008-04-153239, blood-2008-04-153239 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Kohlmann A, Kipps TJ, Rassenti LZ et al (2008) An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase. Br J Haematol 142:802–807. doi: 10.1111/j.1365-2141.2008.07261.x, BJH7261 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Kohlmann A, Grossmann V, Haferlach T (2012) Integration of next-generation sequencing into clinical practice: are we there yet? Semin Oncol 39:26–36. doi: 10.1053/j.seminoncol.2011.11.008, S0093-7754(11)00297- 1 [pii]PubMedCrossRefGoogle Scholar
  20. 20.
    Huang Y, Sitwala K, Bronstein J et al (2012) Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood 119:388–98. doi: 10.1182/blood-2011-03-341081 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Drexler HG (2010) The guide to Leukemia-Lymphoma cell lines, 2nd edn. DSMZ Braunschweig, GermanyGoogle Scholar
  22. 22.
    Shiozawa Y, Havens AM, Pienta KJ, Taichman RS (2008) The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22:941–50. doi: 10.1038/leu.2008.48 PubMedCrossRefGoogle Scholar
  23. 23.
    McMillin DW, Negri JM, Mitsiades CS (2013) The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12:217–28. doi: 10.1038/nrd3870 PubMedCrossRefGoogle Scholar
  24. 24.
    Sison EAR, Rau RE, McIntyre E et al (2013) MLL-rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism. Br J Haematol 160:785–97. doi: 10.1111/bjh.12205 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Sauvageau G, Thorsteinsdottir U, Hough MR et al (1997) Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 6:13–22PubMedCrossRefGoogle Scholar
  26. 26.
    Schmittwolf C, Porsch M, Greiner A et al (2005) HOXB4 confers a constant rate of in vitro proliferation to transduced bone marrow cells. Oncogene 24:561–72. doi: 10.1038/sj.onc.1208202 PubMedCrossRefGoogle Scholar
  27. 27.
    Thorsteinsdottir U, Sauvageau G, Hough MR et al (1997) Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol 17:495–505PubMedCentralPubMedGoogle Scholar
  28. 28.
    Kroon E, Krosl J, Thorsteinsdottir U et al (1998) Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 17:3714–25. doi: 10.1093/emboj/17.13.3714 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Haferlach C, Mecucci C, Schnittger S et al (2009) AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood 114:3024–3032. doi: 10.1182/blood-2009-01-197871, blood-2009-01-197871 [pii]PubMedCrossRefGoogle Scholar
  30. 30.
    Ramsey JM, Kettyle LMJ, Sharpe DJ et al (2013) Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of cytogenetically normal acute myeloid leukemia. Stem Cells 31:1434–45. doi: 10.1002/ stem.1398 PubMedCrossRefGoogle Scholar
  31. 31.
    Wilhelm BT, Briau M, Austin P et al (2011) RNA-seq analysis of 2 closely related leukemia clones that differ in their self-renewal capacity. Blood 117:e27–e38. doi: 10.1182/blood-2010-07-293332, blood-2010-07-293332 [pii]PubMedCrossRefGoogle Scholar
  32. 32.
    Milojkovic D, Apperley J (2008) State-of-the-art in the treatment of chronic myeloid leukaemia. Curr Opin Oncol 20:112–21. doi: 10.1097/CCO.0b013e3282f1fe8a PubMedCrossRefGoogle Scholar
  33. 33.
    Sullivan C, Peng C, Chen Y et al (2010) Targeted therapy of chronic myeloid leukemia. Biochem Pharmacol 80:584–91. doi: 10.1016/ j.bcp.2010.05.001 PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang SD, Gant TW (2009) sscMap: an extensible Java application for connecting small-molecule drugs using gene-expression signatures. BMC Bioinformatics 10:236. doi: 10.1186/1471-2105-10-236, 1471-2105-10-236 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    McArt DG, Zhang S-D (2011) Identification of candidate small-molecule therapeutics to cancer by gene-signature perturbation in connectivity mapping. PLoS One 6:e16382. doi: 10.1371/journal.pone.0016382 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Parmigiani G, Garrett ES, Irizarry RA, Zeger SL (2003) An Overview of Methods and Software. In: The Analysis of Gene Expression Data Statistics for Biology and Health, Springer, New York, pp 1–45. doi:10.1007/0-387-21679-0_1Google Scholar
  37. 37.
    Zhang A (2006) Advanced analysis of gene expression microarray data. World Scientific, SingaporeGoogle Scholar
  38. 38.
    Novershtern N, Subramanian A, Lawton LN et al (2011) Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144:296–309. doi:  10.1016/j.cell.2011.01.004 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Bagger FO, Rapin N, Theilgaard-Mönch K et al (2013) HemaExplorer: a database of mRNA expression profiles in normal and malignant haematopoiesis. Nucleic Acids Res 41:D1034–9. doi: 10.1093/nar/gks1021 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Dickson GJ, Lappin TR, Thompson A (2009) Complete array of HOX gene expression by RQ-PCR. Methods Mol Biol 538:369–93. doi: 10.1007/978-1-59745-418-6_19 PubMedCrossRefGoogle Scholar
  41. 41.
    Srivastava RK, Kurzrock R, Shankar S (2010) MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo. Mol Cancer Ther 9:3254–66. doi: 10.1158/1535-7163.MCT-10-0582 PubMedCrossRefGoogle Scholar
  42. 42.
    Hooker JM, Kim SW, Alexoff D et al (2010) Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography. ACS Chem Neurosci 1:65–73. doi: 10.1021/cn9000268 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Laura M. J. Kettyle
    • 1
  • Fabio G. Liberante
    • 1
  • Alexander Thompson
    • 1
    Email author
  1. 1.Centre for Cancer Research and Cell BiologyQueen’s University BelfastBelfast, Northern IrelandUK

Personalised recommendations