TY - JOUR
T1 - Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
AU - Buchner, Maike
AU - Park, Eugene
AU - Geng, Huimin
AU - Klemm, Lars
AU - Flach, Johanna
AU - Passegué, Emmanuelle
AU - Schjerven, Hilde
AU - Melnick, Ari
AU - Paietta, Elisabeth
AU - Kopanja, Dragana
AU - Raychaudhuri, Pradip
AU - Müschen, Markus
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/3/10
Y1 - 2015/3/10
N2 - Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical course. We show that FOXM1 levels peak at the pre-B-cell receptor checkpoint but are dispensable for normal B-cell development. Compared with normal B-cell populations, FOXM1 levels are 2-to 60-fold higher in ALL cells and are predictive of poor outcome in ALL patients. FOXM1 is negatively regulated by FOXO3A, supports cell survival, drug resistance, colony formation and proliferation in vitro, and promotes leukemogenesis in vivo. Two complementary approaches of pharmacological FOXM1 inhibition-(i) FOXM1 transcriptional inactivation using the thiazole antibiotic thiostrepton and (ii) an FOXM1 inhibiting ARF-derived peptide-recapitulate the findings of genetic FOXM1 deletion. Taken together, our data identify FOXM1 as a novel therapeutic target, and demonstrate feasibility of FOXM1 inhibition in ALL.
AB - Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical course. We show that FOXM1 levels peak at the pre-B-cell receptor checkpoint but are dispensable for normal B-cell development. Compared with normal B-cell populations, FOXM1 levels are 2-to 60-fold higher in ALL cells and are predictive of poor outcome in ALL patients. FOXM1 is negatively regulated by FOXO3A, supports cell survival, drug resistance, colony formation and proliferation in vitro, and promotes leukemogenesis in vivo. Two complementary approaches of pharmacological FOXM1 inhibition-(i) FOXM1 transcriptional inactivation using the thiazole antibiotic thiostrepton and (ii) an FOXM1 inhibiting ARF-derived peptide-recapitulate the findings of genetic FOXM1 deletion. Taken together, our data identify FOXM1 as a novel therapeutic target, and demonstrate feasibility of FOXM1 inhibition in ALL.
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U2 - 10.1038/ncomms7471
DO - 10.1038/ncomms7471
M3 - Article
C2 - 25753524
AN - SCOPUS:84924352841
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 6471
ER -