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.

Acute Leukemias

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

Abstract

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3′-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647–650.

    Article  CAS  Google Scholar 

  2. Gutierrez A, Dahlberg SE, Neuberg DS, Zhang J, Grebliunaite R, Sanda T et al. Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol 2010; 28: 3816–3823.

    Article  CAS  Google Scholar 

  3. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157–163.

    Article  CAS  Google Scholar 

  4. Weng AP, Ferrando AA, Lee W, JPt Morris, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.

    Article  CAS  Google Scholar 

  5. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 2006; 26: 8022–8031.

    Article  CAS  Google Scholar 

  6. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 2006; 103: 18261–18266.

    Article  CAS  Google Scholar 

  7. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20: 2096–2109.

    Article  CAS  Google Scholar 

  8. Hebert J, Cayuela JM, Berkeley J, Sigaux F . Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood 1994; 84: 4038–4044.

    CAS  Google Scholar 

  9. Van Vlierberghe P, Ferrando A . The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest 2012; 122: 3398–3406.

    Article  CAS  Google Scholar 

  10. Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F et al. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med 2011; 208: 1595–1603.

    Article  CAS  Google Scholar 

  11. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203–1210.

    Article  CAS  Google Scholar 

  12. Subramaniam PS, Whye DW, Efimenko E, Chen J, Tosello V, De Keersmaecker K et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell 2012; 21: 459–472.

    Article  CAS  Google Scholar 

  13. Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 2002; 415: 922–926.

    Article  CAS  Google Scholar 

  14. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.

    Article  CAS  Google Scholar 

  15. Ryan JA, Brunelle JK, Letai A . Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci USA 2010; 107: 12895–12900.

    Article  CAS  Google Scholar 

  16. Bassing CH, Swat W, Alt FW . The mechanism and regulation of chromosomal V(D)J recombination. Cell 2002; 109 (Suppl): S45–S55.

    Article  CAS  Google Scholar 

  17. Viret C, Janeway CA Jr. . MHC and T cell development. Rev Immunogenet 1999; 1: 91–104.

    CAS  Google Scholar 

  18. Langenau DM, Jette C, Berghmans S, Palomero T, Kanki JP, Kutok JL et al. Suppression of apoptosis by bcl-2 overexpression in lymphoid cells of transgenic zebrafish. Blood 2005; 105: 3278–3285.

    Article  CAS  Google Scholar 

  19. Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, Chen W et al. Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nat Genet 2002; 31: 135–140.

    Article  CAS  Google Scholar 

  20. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O et al. Selective inhibition of BET bromodomains. Nature 2010; 468: 1067–1073.

    Article  CAS  Google Scholar 

  21. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 2010; 18: 485–498.

    Article  CAS  Google Scholar 

  22. Gutierrez A, Sanda T, Ma W, Zhang J, Grebliunaite R, Dahlberg S et al. Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. Blood 2010; 115: 2845–2851.

    Article  Google Scholar 

  23. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 2007; 204: 1813–1824.

    Article  CAS  Google Scholar 

  24. LaBelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, Lawrence C et al. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest 2012; 122: 2018–2031.

    Article  CAS  Google Scholar 

  25. Nakae J, Barr V, Accili D . Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J 2000; 19: 989–996.

    Article  CAS  Google Scholar 

  26. Davids MS, Letai A . Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol 2012; 30: 3127–3135.

    Article  CAS  Google Scholar 

  27. Jette CA, Flanagan AM, Ryan J, Pyati UJ, Carbonneau S, Stewart RA et al. BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals. Cell Death Differ 2008; 15: 1063–1072.

    Article  CAS  Google Scholar 

  28. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851–1863.

    Article  CAS  Google Scholar 

  29. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011; 146: 904–917.

    Article  CAS  Google Scholar 

  30. Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 2006; 10: 331–342.

    Article  CAS  Google Scholar 

  31. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR . Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 2006; 21: 749–760.

    Article  CAS  Google Scholar 

  32. Manning BD, Cantley LC . AKT/PKB signaling: navigating downstream. Cell 2007; 129: 1261–1274.

    Article  CAS  Google Scholar 

  33. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 2002; 168: 5024–5031.

    Article  CAS  Google Scholar 

  34. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT . c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435: 839–843.

    Article  CAS  Google Scholar 

  35. Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K et al. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol 2010; 12: 372–379.

    Article  CAS  Google Scholar 

  36. Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG et al. BAX activation is initiated at a novel interaction site. Nature 2008; 455: 1076–1081.

    Article  CAS  Google Scholar 

  37. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S et al. Ensembl 2013. Nucleic Acids Res 2013; 41: D48–D55.

    Article  CAS  Google Scholar 

  38. O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998; 17: 384–395.

    Article  CAS  Google Scholar 

  39. Liu JW, Chandra D, Tang SH, Chopra D, Tang DG . Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res 2002; 62: 2976–2981.

    CAS  Google Scholar 

  40. Marani M, Tenev T, Hancock D, Downward J, Lemoine NR . Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002; 22: 3577–3589.

    Article  CAS  Google Scholar 

  41. Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 2005; 436: 807–811.

    Article  CAS  Google Scholar 

  42. Sherr CJ . Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 2006; 6: 663–673.

    Article  CAS  Google Scholar 

  43. Gutierrez A, Feng H, Stevenson K, Neuberg DS, Calzada O, Zhou Y et al. Loss of function tp53 mutations do not accelerate the onset of Myc-induced T-ALL in the zebrafish. Br J Haematol, (in press).

  44. Chonghaile TN, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore VD et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 2011; 334: 1129–1133.

    Article  CAS  Google Scholar 

  45. Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A . BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007; 12: 171–185.

    Article  CAS  Google Scholar 

  46. Vo TT, Ryan J, Carrasco R, Neuberg D, Rossi DJ, Stone RM et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 2012; 151: 344–355.

    Article  CAS  Google Scholar 

  47. Bachmann PS, Piazza RG, Janes ME, Wong NC, Davies C, Mogavero A et al. Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition. Blood 2010; 116: 3013–3022.

    Article  CAS  Google Scholar 

  48. Happo L, Cragg MS, Phipson B, Haga JM, Jansen ES, Herold MJ et al. Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim. Blood 2010; 116: 5256–5267.

    Article  CAS  Google Scholar 

  49. Richter-Larrea JA, Robles EF, Fresquet V, Beltran E, Rullan AJ, Agirre X et al. Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma. Blood 2010; 116: 2531–2542.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health/National Cancer Institute Grant CA167124 and by a grant from the William Lawrence Blanche Hughes Foundation. AG is a Research Fellow of the Gabrielle’s Angel Foundation for Cancer Research. We thank Domenico Accili for the FOXO-D256Δ construct, and Lin He for the MSCV-19a-20-19b construct, both of which were obtained from Addgene. We also thank Dean Felsher for the murine T-ALL cell line 4188.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Gutierrez.

Ethics declarations

Competing interests

LDW is a scientific advisory board member and consultant for Aileron Therapeutics. The Dana-Farber Cancer Institute has filed patents on and licensed drug-like derivatives of JQ1 to Tensha Therapeutics for clinical translation as cancer therapeutics. JEB and the Dana-Farber Cancer Institute have been granted equity (minority) in Tensha, and JEB serves on the Board of Directors. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reynolds, C., Roderick, J., LaBelle, J. et al. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia 28, 1819–1827 (2014). https://doi.org/10.1038/leu.2014.78

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.78

This article is cited by

Search

Quick links