TY - JOUR
T1 - BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia
AU - Hurtz, Christian
AU - Hatzi, Katerina
AU - Cerchietti, Leandro
AU - Braig, Melanie
AU - Park, Eugene
AU - Kim, Yong Mi
AU - Herzog, Sebastian
AU - Ramezani-Rad, Parham
AU - Jumaa, Hassan
AU - Müller, Martin C.
AU - Hofmann, Wolf Karsten
AU - Hochhaus, Andreas
AU - Ye, B. Hilda
AU - Agarwal, Anupriya
AU - Druker, Brian J.
AU - Shah, Neil P.
AU - Melnick, Ari M.
AU - Müschen, Markus
PY - 2011/10/24
Y1 - 2011/10/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80055108071&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80055108071&partnerID=8YFLogxK
U2 - 10.1084/jem.20110304
DO - 10.1084/jem.20110304
M3 - Article
C2 - 21911423
AN - SCOPUS:80055108071
SN - 0022-1007
VL - 208
SP - 2163
EP - 2174
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -