TitleBCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.
Publication TypeJournal Article
Year of Publication2011
AuthorsHurtz, 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, B Ye Hilda, Agarwal Anupriya, Druker Brian J., Shah Neil P., Melnick Ari M., and Müschen Markus
JournalJ Exp Med
Date Published2011 Oct 24
KeywordsAnimals, Antigens, CD34, Benzamides, Cell Survival, Disease Models, Animal, DNA-Binding Proteins, Forkhead Transcription Factors, Hematopoietic Stem Cells, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Transplantation, Neoplastic Stem Cells, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-bcl-6, Pyrimidines, Tumor Cells, Cultured, Tumor Suppressor Protein p53

<p>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.</p>

Alternate JournalJ Exp Med
PubMed ID21911423
PubMed Central IDPMC3201200
Grant ListR37 CA065823 / CA / NCI NIH HHS / United States
R21 CA152497 / CA / NCI NIH HHS / United States
R21CA152497 / CA / NCI NIH HHS / United States
R01 CA157644 / CA / NCI NIH HHS / United States
R01CA137060 / CA / NCI NIH HHS / United States
R01CA139032 / CA / NCI NIH HHS / United States
R01 CA139032 / CA / NCI NIH HHS / United States
R01CA157644 / CA / NCI NIH HHS / United States
P30 CA069533 / CA / NCI NIH HHS / United States
R01 CA137060 / CA / NCI NIH HHS / United States