BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia
Authors: Hurtz Christian , Hatzi Katerina , Cerchietti Leandro , Park Eugene , Kim Yong-Mi , Ramezani-Rad Parham , Jumaa Hassan , Muller Martin C , Hofmann Wolf-Karsten , Hochhaus Andreas , Agarwal Anupriya , Shah Neil , Melnick Ari , Druker Brian J. , Muschen Markus 
Published: October 2019

Abstract 446

Background:

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 (TKI). However, unless CML patients take TKI-treatment life-long, leukemia will eventually recur, which is attributed to the failure of TKI-treatment to eradicate leukemia-initiating cells (LIC; Corbin et al., J Clin Invest 2011). Persistence of LIC in CML can result in acquisition of secondary events eventually leading to TKI-resistant blast crisis, which is fatal within months. Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells (Naka et al., Nature 2010), however the mechanism of FoxO-dependent leukemia-initiation remained elusive.

Results:

Here we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. ChIP-seq analysis demonstrated that BCL6 directly binds to and represses Arf and p53 promoters in human CML cells. Genetic deletion of the BCL6 gene in a mouse model of CML results in progressive depletion of Lin- Sca-1+ c-Kit+ LIC. BCL6-deficient LIC exhibit excessively high expression levels of Arf and p53 and propensity to cellular senescence and apoptosis. As a consequence, BCL-deficient CML cells lack the ability to form colonies and to initiate leukemia in transplant recipient animals. To investigate whether these effects are indeed owing to the role of BCL6 as repressor of Arf/p53, we induced activation of a dominant-negative BCL6-mutant in p53+/+ and p53−/− CML cells. While dominant-negative BCL6 compromised colony formation and self-renewal in p53+/+ CML cells, BCL6 inhibition only had minor effect on p53−/− CML cells. We conclude that BCL6 enables survival of LIC in CML mainly through transcriptional repression of p53.

To test potential clinical relevance of these findings, we used a recently developed retro-inverso BCL6 peptide inhibitor (RI-BPI, Cerchietti et al., 2009), which inhibits BCL6 function as transcriptional repressor. RI-BPI is currently under clinical trial for the treatment of BCL6-dependent diffuse large B cell lymphoma (Dr. Ari Melnick, LLS TAP Program). Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in transplant recipients and selectively eradicates CD34+ CD38− LIC in patient-derived CML samples.

Conclusions:

These findings identify pharmacological inhibition of BCL6 as a novel strategy to eradicate LIC 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. Based on these findings, we propose a dual targeting strategy, in which (1) tyrosine kinase inhibitors (e.g. Imatinib) to target the transient amplifying pool of CML cells are coupled with (2) BCL6 inhibition that will target quiescent LIC.

Disclosures:

Hochhaus: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding. Druker:Novartis: ; Bristol-Myers Squibb: ; ARIAD Pharmaceuticals: ; OHSU patent #843: Mutated ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership.