Reference Report

Reference
Citation	Osman, D., Gobert, V., Ponthan, F., Heidenreich, O., Haenlin, M., Waltzer, L. (2009). A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. Proc. Natl. Acad. Sci. U.S.A. 106(29): 12043--12048. (Export to RIS)
FlyBase ID	FBrf0208349
Publication Type	Research paper
PubMed ID	19581587
PubMed Abstract	The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ(+) progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.
DOI	10.1073/pnas.0902449106
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Proc. Natl. Acad. Sci. U.S.A.
Title	Proceedings of the National Academy of Sciences of the United States of America
Publication Year	1915-
ISBN/ISSN	0027-8424
Data from Reference
Aberrations (1)
	Df(3L)CalpB^-
Alleles (12)
	Avic\GFP^Scer\UAS.cUa Bc¹ CalpB^e04062 CalpB^NIG.cUa Hsap\RUNX1::Hsap\RUNX1T1^Scer\UAS.cMa Hsap\RUNX1^{ΔETO.Scer\UAS.T:Zzzz\nls1} Hsap\RUNX1T1^Scer\UAS.cOa lz^Scer\UAS.cBa Scer\GAL4^lz-gal4 Scer\GAL4^srp.D.cCa Scer\GAL80^ts.αTub84B w^+mC
Constructs (8)
	P{NIG.CalpB.U} P{srpD-GAL4.C} P{tubP-GAL80^ts} P{UAS-ETO.O} P{UAS-GFP.U} P{UAS-Hsap\RUNX1::Hsap\RUNX1T1.M} P{UAS-Hsap\RUNX1.ΔETO} P{UAS-lz.B}
Genes (12)
	Avic\GFP Bc CalpB crq Hsap\RUNX1 Hsap\RUNX1::Hsap\RUNX1T1 Hsap\RUNX1T1 lz proPO45 Scer\GAL4 Scer\GAL80 w
Insertions (3)
	P{GawB}lz^gal4 PBac{RB}CalpB^e04062 PBac{RB}CG6709^e02786
Natural transposons (1)
	P-element