AML1-ETO (aka RUNX1-ETO and RUNX1-MTG8) is a DNA binding transcription factor encoded by a fusion gene generated from t(8;21)(q22;q22). This chromosomal translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in over 10% of all cases. Our own studies and those of others have demonstrated that AML1-ETO plays an important role in the development of leukemia. However, it is not sufficient by itself for leukemia development. We demonstrated that one isoform of t(8;21) fusion protein AML1-ETO9a, which lacks 178 amino acids comprising the C-terminus of the full length AML1- ETO, is highly leukemogenic in a mouse model of retrovirus vector mediated transduction-hematopoietic cell transplantation. Using combined gene expression profiling and promoter occupancy profiling, we have identified a group of direct target genes of AML1-ETO9a in leukemia initiating cells and revealed the therapeutic potential of targeting the JAK-STAT signaling pathway in treatment of the t(8;21) AML. One interesting target is the tumor suppressor gene Ras association domain family member 2 (RASSF2). Aberrant transcriptional repression of RASSF2 is a frequently occurring event in many cancer types, however its involvement in leukemia development remains unexamined. More recently, it has been shown that at the single cell level t(8;21)+ leukemia stem cells at diagnosis have an over 100 fold higher amount of AML1-ETO transcript compared with t(8;21)+ hematopoietic stem cells in remission. Interestingly, no corresponding increase in wild type AML1 transcript is observed. These findings lead to the hypothesis that the enhanced alterations of the AML1-ETO target gene expression via the increased amount of t(8;21) fusion protein is critical for development of the t(8:21)+ AML. Understanding the regulation of AML1-ETO expression and the associated effect of its target genes may provide valuable insight into the molecular mechanisms of leukemogenesis and contribute to rational therapeutic drug design for treating related malignancies. Furthermore, a highly reproducible germline transmitted mouse model of the t(8;21) AML will be valuable for mechanistic studies and therapeutic evaluations. We have developed three specific aims to test this hypothesis.
Specific Aim #1 will analyze the effect of t(8;21) on leukemogenesis and hematopoiesis using a new model of AML1-ETO9a transgenic mice.
Specific Aim #2 will study the effect of t(8;21) on leukemogenesis by characterizing its direct target RASSF2.
Specific Aim #3 will examine the molecular mechanisms of increased AML1-ETO expression during leukemia development.

Public Health Relevance

Acute myeloid leukemia is a major form of the blood cancer with very few targeted therapies. Over 50% of patients, who responded to initial chemotherapies, relapsed within five years and die from this disease. The aim of this application is to study to provide molecular insights into acute myeloid leukemia to better develop novel and effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104509-13
Application #
9298590
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2004-07-16
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Marneth, Anna E; Botezatu, Lacramioara; Hönes, Judith M et al. (2018) GFI1 is required for RUNX1/ETO positive acute myeloid leukemia. Haematologica 103:e395-e399
Yan, F; Shen, N; Pang, J X et al. (2017) Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia 31:1434-1442
Gao, X N; Yan, F; Lin, J et al. (2015) AML1/ETO cooperates with HIF1? to promote leukemogenesis through DNMT3a transactivation. Leukemia 29:1730-40
DeKelver, Russell C; Lewin, Benjamin; Weng, Stephanie et al. (2014) RUNX1-ETO induces a type I interferon response which negatively effects t(8;21)-induced increased self-renewal and leukemia development. Leuk Lymphoma 55:884-91
Lo, M-C; Peterson, L F; Yan, M et al. (2013) JAK inhibitors suppress t(8;21) fusion protein-induced leukemia. Leukemia 27:2272-9
DeKelver, Russell C; Yan, Ming; Ahn, Eun-Young et al. (2013) Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential. Blood 121:3714-7
DeKelver, Russell C; Lewin, Benjamin; Lam, Kentson et al. (2013) Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia. PLoS Genet 9:e1003765
Lo, Miao-Chia; Peterson, Luke F; Yan, Ming et al. (2012) Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML. Blood 120:1473-84
Shia, Wei-Jong; Okumura, Akiko J; Yan, Ming et al. (2012) PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. Blood 119:4953-62
Arnold, Christopher P; Tan, Ruoying; Zhou, Baiyu et al. (2011) MicroRNA programs in normal and aberrant stem and progenitor cells. Genome Res 21:798-810

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