Previously, I was awarded the Outstanding Investigator award for two terms before the Program at NCI was discontinued. I have continued to be extremely productive to these days. My H index is 179 and I am one of the most cited scientists in the world. I have published more than 1000 articles in peer reviewed journals. I have also made many important discoveries in cancer genetics and have identified and characterized many cancer genes. My discoveries that changed the ways to think about cancer, I believe, are: the demonstration of the juxtaposition of the MYC oncogene to the immunoglobulin loci and its dysregulation in Burkitt lymphoma, the first demonstration of the specific gene alterations in human cancer. The discovery of the BCL2 gene and its involvement in follicular lymphoma and in other malignancies. The Bcl2 protein is now targeted by ABT199, a drug of Abbott that causes complete remission in patients with CLL. BCL2 is the prototype of a large family of genes that control programmed cell death, or apoptosis. The discovery of ALL1, now renamed MLL1, a gene involved in more than 50 different translocations in ALL and AML. Its dysregulation in cancer affects chromatin structure. I also discovered the partial duplication of ALL1 (MLL1) in AML. I also discovered TCL1, which is responsible for 98% of human pre T cell leukemias, and that this gene is dysregulated in most of the aggressive CLLs. I have also discovered the role of translocations involving the T cell receptor in T cell malignancies. I also generated transgenic and KO mice to validate the oncogenes and tumor suppressor genes we discovered. It was thought that all cancer genes were encoding protein products. The dogma was that only protein coding genes that represent only 2% of the human genome were important and the remaining 98% was junk. This view was shattered by my discovery in 2002 that CLL is caused by the loss of two microRNA genes on chromosome 13q14, miR-15a and miR-16-1. Thus genes encoding non coding RNAs can also be involved in cancer pathogenesis. We also found that these two microRNAs target BCL2, the gene I discovered in 1984. We also discovered germline and somatic mutations in microRNA genes in human malignancies and that microRNAs are dysregulated in all cancers, primarily because several of them are downstream targets of pathways responsible for oncogenesis. More recently, we discovered that tumors such as lung cancer and pancreatic cancer secrete microvesicles that fuse with macrophages and dendritic cells. MiR-21 that is contained in such microvesicles is internalized, reaches the endosomes of the recipient cells and binds and activates Toll Like Receptor 8 in humans and 7 (it's homologue) in the mouse, activating the receptor. Then NF-?B is activated and IL6 and TNFalpha are secreted, facilitating tumor spreading and metastatic disease. This year we showed that fusion of microvesicles with myoblasts causes cachexia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197706-06
Application #
9998898
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Klauzinska, Malgorzata
Project Start
2015-09-11
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Ohio State University
Department
Genetics
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Galasso, Marco; Morrison, Carl; Minotti, Linda et al. (2018) Loss of miR-204 expression is a key event in melanoma. Mol Cancer 17:71
Pekarsky, Yuri; Balatti, Veronica; Croce, Carlo M (2018) BCL2 and miR-15/16: from gene discovery to treatment. Cell Death Differ 25:21-26
Pagotto, Sara; Veronese, Angelo; Soranno, Alessandra et al. (2018) Hsa-miR-155-5p drives aneuploidy at early stages of cellular transformation. Oncotarget 9:13036-13047
Balatti, Veronica; Tomasello, Luisa; Rassenti, Laura Z et al. (2018) miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood 132:2179-2182
Fong, Louise Y; Jing, Ruiyan; Smalley, Karl J et al. (2018) Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats. Proc Natl Acad Sci U S A 115:E11091-E11100
Martín-López, Juana; Gasparini, Pierluigi; Coombes, Kevin et al. (2018) Mutation of TGF?-RII eliminates NSAID cancer chemoprevention. Oncotarget 9:12554-12561
Kim, Taewan; Croce, Carlo M (2018) Long noncoding RNAs: Undeciphered cellular codes encrypting keys of colorectal cancer pathogenesis. Cancer Lett 417:89-95
Pi, Fengmei; Binzel, Daniel W; Lee, Tae Jin et al. (2018) Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat Nanotechnol 13:82-89
Ngankeu, Apollinaire; Ranganathan, Parvathi; Havelange, Violaine et al. (2018) Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia. Oncotarget 9:4354-4365
Fong, Louise Y; Jing, Ruiyan; Smalley, Karl J et al. (2017) Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia. Oncotarget :

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