Mechanisms of aberrant transcription of EVI1 in acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).
Final Report Abstract
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.
Publications
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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, Stefan; Sanders, Mathijs A.; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A.M.; Erpelinck, Claudia; van der Velden, Vincent H.J.; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J.; van Duin, Mark; Döhner, Konstanze; Beverloo, H. Berna; Bradner, James E.; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J.M.; Bindels, Eric M.J.; ... & Delwel, Ruud
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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, Stefan; Sanders, Mathijs A.; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A.M.; Erpelinck, Claudia; van der Velden, Vincent H.J.; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J.; van Duin, Mark; Döhner, Konstanze; Beverloo, H. Berna; Bradner, James E.; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J.M.; Bindels, Eric M.J.; ... & Delwel, Ruud
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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, Stefan; Sanders, Mathijs A.; Hoogenboezem, Remco; Zeilemaker, Annelieke; Havermans, Marije; Erpelinck, Claudia; Bindels, Eric M. J.; Beverloo, H. Berna; Döhner, Hartmut; Löwenberg, Bob; Döhner, Konstanze; Delwel, Ruud & Valk, Peter J. M.
