AML is a devastating blood tumor, the most common type of leukemia in adults, a disease that continues to have the lowest survival rate within leukemia. Nearly 45,000 people are diagnosed each year in the US, and the current 5-year survival frequency is only 24% with an almost 50% relapse rate after treatment. AML is a part of a wider family of myeloid neoplasms that include diverse but related diseases like myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), a disease that frequently develops into AML. Currently, there are no targeted therapies for most of these diseases, including AML, making the study of the molecular mechanisms of their induction and progression of great significance. We have recently identified novel somatically acquired mutations inactivating the Notch signaling pathway in patients with CMML. Interestingly, these Notch mutations do not act in isolation but they co-occur with additional genomic hits, including mutations on the TET2, ASXL1, KRAS and JAK2 genes. Our published and preliminary data presented here demonstrate that: a) The Notch pathway is switched-off in myelo-monocytic leukemias, including AML, b) Inhibition of the pathway is achieved both by inactivating mutations and epigenetic silencing, c) Re-activation of the pathway can inhibit the growth of mouse CMML in vivo and human AML in vitro. In this application we: a) Assess the biological effects of Notch pathway re- activation in AML, b) Identify the molecular and epigenetic mode of pathway inhibition in human AML and c) Study co-operation of Notch pathway mutations with additional genomic lesions and their effect in AML initiation and progression. We strongly believe that these studies can lead to future targeted therapies of AML and related myeloid neoplasms, as re-activation of the Notch pathway can be achieved using both peptide and antibody agonist approaches.

Public Health Relevance

Acute myeloid leukemia (AML) is a devastating blood tumor with no identified targeted therapy. In this proposal we combine genetic and genomic approaches to understand and target leukemia initiation and progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA169784-05
Application #
9398105
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Duglas Tabor, Yvonne
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Gong, Yixiao; Lazaris, Charalampos; Sakellaropoulos, Theodore et al. (2018) Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries. Nat Commun 9:542
Cimmino, Luisa; Neel, Benjamin G; Aifantis, Iannis (2018) Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol 28:698-708
Gong, Yixiao; Huang, Hsuan-Ting; Liang, Yu et al. (2017) lncRNA-screen: an interactive platform for computationally screening long non-coding RNAs in large genomics datasets. BMC Genomics 18:434
Wang, Eric; Aifantis, Ioannis (2017) Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite. Cancer Discov 7:1065-1066
Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao et al. (2017) Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 170:1079-1095.e20
Cimmino, Luisa; Aifantis, Iannis (2017) Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev 42:1-7
Valls, Ester; Lobry, Camille; Geng, Huimin et al. (2017) BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells. Cancer Discov 7:506-521
King, Bryan; Boccalatte, Francesco; Moran-Crusio, Kelly et al. (2016) The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells. Nat Immunol 17:1312-1321
Guryanova, Olga A; Shank, Kaitlyn; Spitzer, Barbara et al. (2016) DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22:1488-1495
Aranda-Orgilles, Beatriz; SaldaƱa-Meyer, Ricardo; Wang, Eric et al. (2016) MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis. Cell Stem Cell 19:784-799

Showing the most recent 10 out of 47 publications