Klin Padiatr 2017; 229(03): 182-195
DOI: 10.1055/s-0037-1602194
Top 1 Acute and chronic leukaemias
Georg Thieme Verlag KG Stuttgart · New York

FOXM1 haploinsufficiency in acute lymphoblastic leukemia

S Raasch
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
A Bronsema
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
J Müller
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
J Strauss
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
M Eschenburg
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
U Zur Stadt
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
,
I Vater
2   Institute of Human Genetics, UK-SH Campus Kiel, Kiel, Germany
,
R Siebert
2   Institute of Human Genetics, UK-SH Campus Kiel, Kiel, Germany
,
MA Horstmann
1   Research Institute Children's Cancer Center Hamburg and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
30 May 2017 (online)

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    Introduction:

    The ETV6/RUNX1 (TEL/AML1) fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL) and results in a t(12;21)(p13;q22) chromosomal translocation. ETV6/RUNX1 per se is not leukemogenic but predisposes leukemogenesis in patients. Break point analysis of predominant deletions revealed RAG1/2 consensus sites, including an aberrant RAG1/2 activity. The underlying mechanism is still unclear. We propose a DNA repair deficiency due to hemizygous loss of FOXM1 on the fragile 12p13.3, apparently not targeted by RAG1/2. FOXM1 is a transcription factor involved in cell cycle control including mitotic fidelity and presumably DNA repair.

    Methods and Results:

    Matched pair mapping of gene activity showed a downregulation of FoxM1 in ALL compared to immunological matched progenitors. Utilizing a variety of different methodologies we identified monoallelic deletions of FOXM1 mostly in coincidence with hemizygous deletions of TEL on 12p13. Under the hypothesis of FOXM1 as a haploinsufficient 12 p tumor suppressor we established various conditional mouse models, in which a Foxm1 knock-out could be combined with a monoallelic Etv6-RUNX1 knock-in upon Cre recombinase activity. We observed an induction of acute leukemias (T-ALL/AML) in 60% of Foxm1-/+/Etv6-RUNX1-/+ mice and in 30% of Foxm1-/- mice. In line with the notion of a critical role in DNA repair, we observed a downregulation of DNA damage sensors Csk1, Nbs1 and Skp2 at the transcriptional level of Foxm1-/- cells.

    Conclusion:

    Taken together, we propose FOXM1 as a haploinsufficient 12 p tumor suppressor in the context of Etv6-RUNX1. The mutation signature of Foxm1-/+/Etv6-RUNX1-/+ ALL will be assessed by WGS, exome and RNA sequencing.


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    No conflict of interest has been declared by the author(s).