Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia

Maike Buchner; Eugene Park; Huimin Geng; Lars Klemm; Johanna Flach; Emmanuelle Passegué; Hilde Schjerven; Ari Melnick; Elisabeth Paietta; Dragana Kopanja; Pradip Raychaudhuri; Markus Müschen

doi:10.1038/ncomms7471

Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia

Maike Buchner, Eugene Park, Huimin Geng, Lars Klemm, Johanna Flach, Emmanuelle Passegué, Hilde Schjerven, Ari Melnick, Elisabeth Paietta, Dragana Kopanja, Pradip Raychaudhuri, Markus Müschen

Medicine

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

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.

Original language	English (US)
Article number	6471
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7471
State	Published - Mar 10 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms7471

Fingerprint Dive into the research topics of 'Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia'. Together they form a unique fingerprint.

Cite this

Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. / Buchner, Maike; Park, Eugene; Geng, Huimin; Klemm, Lars; Flach, Johanna; Passegué, Emmanuelle; Schjerven, Hilde; Melnick, Ari; Paietta, Elisabeth; Kopanja, Dragana; Raychaudhuri, Pradip; Müschen, Markus.

In: Nature communications, Vol. 6, 6471, 10.03.2015.

Research output: Contribution to journal › Article › peer-review

@article{1b5966552e2e4befa6edf3d82dd73889,

title = "Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia",

abstract = "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.",

author = "Maike Buchner and Eugene Park and Huimin Geng and Lars Klemm and Johanna Flach and Emmanuelle Passegu{\'e} and Hilde Schjerven and Ari Melnick and Elisabeth Paietta and Dragana Kopanja and Pradip Raychaudhuri and Markus M{\"u}schen",

note = "Funding Information: We thank Dr Hassan Jumaa, Ulm, Germany and Dr Kevin Shannon, San Francisco, CA for critical discussions. This work was supported by grants from the NIH/NCI through R01CA137060, R01CA139032, R01CA169458, R01CA172558 and R01CA157644 (to M.M.), grants from the Leukemia and Lymphoma Society (to M.M.), the California Institute for Regenerative Medicine through TR02-1816 (M.M.), the William Lawrence and Blanche Hughes Foundation and a Leukaemia Lymphoma Research project grant (to M.M.). M.M. is a Scholar of The Leukemia and Lymphoma Society and a Wellcome Trust Senior Investigator. P.R. is supported by NCI grants CA175380 and CA177655.",

year = "2015",

month = mar,

day = "10",

doi = "10.1038/ncomms7471",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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 - Funding Information: We thank Dr Hassan Jumaa, Ulm, Germany and Dr Kevin Shannon, San Francisco, CA for critical discussions. This work was supported by grants from the NIH/NCI through R01CA137060, R01CA139032, R01CA169458, R01CA172558 and R01CA157644 (to M.M.), grants from the Leukemia and Lymphoma Society (to M.M.), the California Institute for Regenerative Medicine through TR02-1816 (M.M.), the William Lawrence and Blanche Hughes Foundation and a Leukaemia Lymphoma Research project grant (to M.M.). M.M. is a Scholar of The Leukemia and Lymphoma Society and a Wellcome Trust Senior Investigator. P.R. is supported by NCI grants CA175380 and CA177655.

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.

UR - http://www.scopus.com/inward/record.url?scp=84924352841&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924352841&partnerID=8YFLogxK

U2 - 10.1038/ncomms7471

DO - 10.1038/ncomms7471

M3 - Article

C2 - 25753524

AN - SCOPUS:84924352841

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6471

ER -