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DOI: 10.1055/s-0037-1602194
FOXM1 haploinsufficiency in acute lymphoblastic leukemia
Publikationsverlauf
Publikationsdatum:
30. Mai 2017 (online)
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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Die Autoren geben an, dass kein Interessenkonflikt besteht.