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.
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.
|Ntziachristos, Panagiotis; Abdel-Wahab, Omar; Aifantis, Iannis (2016) Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol 17:1016-24|
|Guryanova, O A; Lieu, Y K; Garrett-Bakelman, F E et al. (2016) Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 30:1133-42|
|Cimmino, Luisa; Aifantis, Iannis (2016) Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev 42:1-7|
|Inoue, Satoshi; Li, Wanda Y; Tseng, Alan et al. (2016) Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell 30:337-48|
|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|
|Coombs, Catherine C; Sallman, David A; Devlin, Sean M et al. (2016) Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. Haematologica 101:e457-e460|
|Guillamot, Maria; Cimmino, Luisa; Aifantis, Iannis (2016) The Impact of DNA Methylation in Hematopoietic Malignancies. Trends Cancer 2:70-83|
|Aranda-Orgilles, Beatriz; SaldaÃ±a-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|
|Kourtis, Nikos; Moubarak, Rana S; Aranda-Orgilles, Beatriz et al. (2015) FBXW7 modulates cellular stress response and metastatic potential through â€‹HSF1 post-translational modification. Nat Cell Biol 17:322-32|
|Cimmino, Luisa; Dawlaty, Meelad M; Ndiaye-Lobry, Delphine et al. (2015) TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol 16:653-62|
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