Mechanismen der aberranten Transkription des Proto-Onkogens EVI1 in der akuten myeloischen Leukämie mit inv(3)(q21q26.2) oder t(3;3)(q21;q26.2).
Zusammenfassung der Projektergebnisse
In summary, wecould identify a small, commonly altered region corresponding to an enhancer region found to directly bind the EVI1 promotor in inv(3)/t(3;3) AML, as proposed in the original grant application. Enrichment of H3K27-ac enhancer marks suggest that it may act as a super-enhancer. The tumor-suppressor and key myeloid transcript GATA2 was revealed to be regulated by this same enhancer region on chromosome 3. The characteristic leukemogenic translocations on chromosome 3 thus result in a functional haplo-insufficiency of an otherwise wild-type GATA2. The WHO AML inv(3)/t(3;3)/RPN1-EVI1 is now considered for reclassification into inv(3)/t(3;3)/GATA2-EVI1 based on these observations made both in human and mice by us and others. We propose that such events are likely to be highly prevalent in a wide range of tumor entities. We could show that control of oncogene expression by this type of enhancers is a likely operative pathogenic pathway that might allow for developments of novel strategies for detection and treatment.
Projektbezogene Publikationen (Auswahl)
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19th Congress of the European Hematology Association, Italy, Milan, 2014. Presidential Symposium. “A single oncogenic enhancer-rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.”
Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, van der Velden VHJ, Havermans M, Avellino R, van Lom K, Rombouts EJ, van Duin M, Döhner K, Beverloo HB, Bradner JE, Döhner H, Löwenberg B, Valk PJM, Bindels EMJ, de Laat W, Delwel R
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56th American Society of Hematology Annual Meeting and Exposition, San Francisco, USA, 2014. “A Myeloid-Specific Gene-Dosage Regulator for CEBPA Expression in Myeloid Cells Is Commonly Targeted By Onco-Proteins in AML.”
Roberto Avellino, Stefan Gröschel, Harmen Van de Werken, Mathijs A. Sanders, Remco M. Hoogenboezem, Claudia Erpelinck, Marije Havermans, Eric Bindels, Ruud Delwel
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56th American Society of Hematology Annual Meeting and Exposition, San Francisco, USA, 2014. “Defects in the RAS/RTK Signaling Pathways Predominate the Mutational Spectrum of EVI1/GATA2 Rearranged Myeloid Malignancies with Inv(3)/t(3;3).”
Sanders MA, Gröschel S, Hoogenboezem R, Zeilemaker A, Havermans M, Erpelinck C, Bindels EMJ, Beverloo HB, Döhner H, Löwenberg B, Döhner K, Delwel R, Valk PJM
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A single oncogenic enhancer rearrangement causes concomitant deregulation of EVI1 and GATA2 in leukemia. Cell 2014 Apr 10; 157(2):369-81
Gröschel S, Sanders M, Hoogenboezem R, de Wit E, Bouwman B, Erpelinck C, van der Velden V, Havermans M, Avellino R, van Lom K, Rombouts E, van Duin M, Döhner K, Beverloo B, Bradner J, Döhner H, Löwenberg B, Valk P, Bindels E, de Laat W, Delwel R
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Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. Blood 2014 Nov 7 [Epub ahead of print]
Gröschel S, Sanders MA, Hoogenboezem R, Zeilemaker A, Havermans M, Erpelinck C, Bindels EMJ, Beverloo HB, Döhner H, Löwenberg B, Döhner K, Delwel R, Valk PJM
