BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia

Christian Hurtz, Katerina Hatzi, Leandro Cerchietti, Melanie Braig, Eugene Park, Yong Mi Kim, Sebastian Herzog, Parham Ramezani-Rad, Hassan Jumaa, Martin C. Müller, Wolf Karsten Hofmann, Andreas Hochhaus, B. Hilda Ye, Anupriya Agarwal, Brian Druker, Neil P. Shah, Ari M. Melnick, Markus Müschen

Research output: Contribution to journalArticle

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Abstract

Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34 + CD38 - LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.

Original languageEnglish (US)
Pages (from-to)2163-2174
Number of pages12
JournalJournal of Experimental Medicine
Volume208
Issue number11
DOIs
StatePublished - Oct 24 2011

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cell Survival
Leukemia
Stem Cells
Protein-Tyrosine Kinases
Myeloid Cells
Blast Crisis
Lymphocyte Activation
Therapeutics
Maintenance
Pharmacology
Peptides

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Hurtz, C., Hatzi, K., Cerchietti, L., Braig, M., Park, E., Kim, Y. M., ... Müschen, M. (2011). BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal of Experimental Medicine, 208(11), 2163-2174. https://doi.org/10.1084/jem.20110304

BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. / Hurtz, Christian; Hatzi, Katerina; Cerchietti, Leandro; Braig, Melanie; Park, Eugene; Kim, Yong Mi; Herzog, Sebastian; Ramezani-Rad, Parham; Jumaa, Hassan; Müller, Martin C.; Hofmann, Wolf Karsten; Hochhaus, Andreas; Ye, B. Hilda; Agarwal, Anupriya; Druker, Brian; Shah, Neil P.; Melnick, Ari M.; Müschen, Markus.

In: Journal of Experimental Medicine, Vol. 208, No. 11, 24.10.2011, p. 2163-2174.

Research output: Contribution to journalArticle

Hurtz, C, Hatzi, K, Cerchietti, L, Braig, M, Park, E, Kim, YM, Herzog, S, Ramezani-Rad, P, Jumaa, H, Müller, MC, Hofmann, WK, Hochhaus, A, Ye, BH, Agarwal, A, Druker, B, Shah, NP, Melnick, AM & Müschen, M 2011, 'BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia', Journal of Experimental Medicine, vol. 208, no. 11, pp. 2163-2174. https://doi.org/10.1084/jem.20110304
Hurtz, Christian ; Hatzi, Katerina ; Cerchietti, Leandro ; Braig, Melanie ; Park, Eugene ; Kim, Yong Mi ; Herzog, Sebastian ; Ramezani-Rad, Parham ; Jumaa, Hassan ; Müller, Martin C. ; Hofmann, Wolf Karsten ; Hochhaus, Andreas ; Ye, B. Hilda ; Agarwal, Anupriya ; Druker, Brian ; Shah, Neil P. ; Melnick, Ari M. ; Müschen, Markus. / BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 11. pp. 2163-2174.
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