GATA1 mutations are not a hallmark of acute myeloid leukaemia with t(8;21)
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Abstract:
Leukaemogenesis is a stepwise process of a delimited number of genetic aberrations, which lead to maturation impairment and promote proliferation and/or survival of the neoplastic clone.1 In acute myeloid leukaemia (AML) with t(8;21)(q22;q22)/ RUNX1-RUNX1T1 , genetic aberrations additional to the core-binding factor rearrangement are well known.2 Presumably further aberrations are also involved in leukaemogenesis of such AML, but are yet to be discovered.
Decrease/loss of function of the transcription factor GATA1 plays a central role in transient myeloproliferative disorders (TMDs) of newborns with trisomy 21.3–6 The presence of a short protein isoform, generated by a mutation, is complementary to trisomy 21 to initiate TMD.6 7 Since the potent oncogene RUNX1 is located …Keywords:
RUNX1
GATA1
Trisomy
Core binding factor
Myeloproliferative Disorders
clone (Java method)
SUMMARY Hematopoietic stem cells (HSCs) emerge from hemogenic endothelium (HE) localised in the embryonic dorsal aorta (DA). Here we show that Runx1, a transcription factor essential for HSC emergence, controls HE establishment in the absence of its non-DNA-binding partner, CBFβ, and that a CBFβ-binding-deficient Runx1 mutant form can activate the HE program in the DA. Nevertheless, CBFβ is also essential for HSC emergence by regulating the specification of definitive hemangioblasts (DHs), the precursors of the DA and HE, in the lateral plate mesoderm where it mediates VEGFA induction by BMP signalling. Surprisingly, no Runx gene is expressed in DHs and the pharmacological inhibition of CBFβ binding to Runx is not detrimental for DH, confirming that CBFβ functions independently of Runx. Thus, we have uncovered, for the first time, that CBFβ regulates gene expression without Runx, breaking the dogma in which CBFβ ‘s gene regulatory functions are strictly dependent on its binding to Runx. HIGHLIGHTS Runx1 and CBFβ play independent roles in the establishment of the HSC lineage Runx1 binding to CBFβ is not required for HE establishment CBFβ is downstream of BMP and regulates endogenous VEGFA expression in DH Binding to Runx is not obligatory for CBFβ function
RUNX1
Core binding factor
Hemangioblast
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Abstract The core binding factor (CBF) transcription factor complex regulates coding and non-coding genes that play a critical role in hematopoiesis. Chromosomal rearrangements involving the two CFB subunits, RUNX1 and CFB beta, are common in acute myeloid leukemia (AML). The fusion proteins resulting from these rearrangements deregulate the transcription of RUNX1-target genes, including microRNAs critical for KIT-mediated proliferation (e.g. miR-221) and myeloid differentiation (e.g. miR-223). We found that overexpression of miR-17, which downregulates RUNX1 level by targeting RUNX1-UTR, recapitulates the biological effects of CBF-AML fusion proteins by affecting the transcription of common coding and non-coding RUNX1-targets. Consistently, increased levels of miR-17 can be detected in AML patient samples displaying increased KIT level, but without evidence of CBF mutations. Based on these finding, we propose that the definition of CBF-AML leukemia can be expanded to accommodate leukemia induced not only by genetic factors but also epigenetic factors, such as microRNAs targeting RUNX1. Acknowledgements: Funding for this study was provided by a Roswell Park Alliance Foundation award, the University of Rochester-RPCI pilot grant, and the Mark Diamond Research Fund. Citation Format: John A. Fischer, Stefano Rossetti, Arani Datta, Alessandro Beghini, Nicoletta Sacchi. Expanding the definition of core binding factor leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 180. doi:10.1158/1538-7445.AM2015-180
RUNX1
Core binding factor
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Core binding factor
RUNX1
Penetrance
Conditional gene knockout
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RUNX1
Core binding factor
RUNX2
Hemangioblast
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Highlights•Small molecule inhibitors of CBFβ-RUNX protein-protein interaction developed.•Inhibitors alter occupancy of RUNX1 on target genes and alter their expression.•Inhibitors show efficacy against leukemia cell lines and basal-like (triple negative) breast cancer cell lines.Transcription factors are proteins that bind to DNA and regulate how much of other proteins are made. We describe the development of inhibitors of the interaction between two transcription factors, CBFβ and RUNX. Both these transcription factors are the targets of alterations in human leukemia as well as in a number of solid tumors. The inhibitor changes the behavior of the RUNX transcription factor and alters the levels of proteins it regulates. We show these inhibitors may have potential utility for leukemia as well as one specific type of breast cancer which has a very poor prognosis.AbstractTranscription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could more effectively address the stem cell like properties, such as self-renewal and chemo-resistance, that lead to the failure of traditional chemotherapy approaches. Core binding factor is a heterodimeric transcription factor comprised of one of 3 RUNX proteins (RUNX1-3) and a CBFβ binding partner. CBFβ enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFβ are frequently mutated in human leukemia. More recently, RUNX proteins have been shown to be key players in epithelial cancers, suggesting the targeting of this pathway could have broad utility. In order to test this, we developed small molecules which bind to CBFβ and inhibit its binding to RUNX. Treatment with these inhibitors reduces binding of RUNX1 to target genes, alters the expression of RUNX1 target genes, and impacts cell survival and differentiation. These inhibitors show efficacy against leukemia cells as well as basal-like (triple-negative) breast cancer cells. These inhibitors provide effective tools to probe the utility of targeting RUNX transcription factor function in other cancers.Graphical abstract
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RUNX1
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RUNX1
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Core binding factor
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Core binding factor
RUNX1
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Core binding factor
RUNX1
RUNX1T1
breakpoint cluster region
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