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 M. Paietta, Dragana Kopanja, Pradip Raychaudhuri, Markus Müschen

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Article number6471
JournalNature Communications
Volume6
DOIs
StatePublished - Mar 10 2015

Fingerprint

leukemias
Cell Lineage
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Cells
Pre-B Cell Receptors
Thiostrepton
Thiazoles
Therapeutics
deletion
prognosis
antibiotics
Anti-Bacterial Agents
Peptides
Drug Resistance
deactivation
peptides
Cell Survival
drugs
Pharmaceutical Preparations

ASJC Scopus subject areas

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

Cite this

Buchner, M., Park, E., Geng, H., Klemm, L., Flach, J., Passegué, E., ... Müschen, M. (2015). Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. Nature Communications, 6, [6471]. https://doi.org/10.1038/ncomms7471

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 M.; Kopanja, Dragana; Raychaudhuri, Pradip; Müschen, Markus.

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

Research output: Contribution to journalArticle

Buchner, M, Park, E, Geng, H, Klemm, L, Flach, J, Passegué, E, Schjerven, H, Melnick, A, Paietta, EM, Kopanja, D, Raychaudhuri, P & Müschen, M 2015, 'Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia', Nature Communications, vol. 6, 6471. https://doi.org/10.1038/ncomms7471
Buchner, Maike ; Park, Eugene ; Geng, Huimin ; Klemm, Lars ; Flach, Johanna ; Passegué, Emmanuelle ; Schjerven, Hilde ; Melnick, Ari ; Paietta, Elisabeth M. ; Kopanja, Dragana ; Raychaudhuri, Pradip ; Müschen, Markus. / Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. In: Nature Communications. 2015 ; Vol. 6.
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