Faculty : Faculty

Luisa Cimmino, Ph.D.

Assistant Professor
Primary Appointment of Biochemistry and Molecular Biology
(305) 243-0208
luisa.cimmino@med.miami.edu
BRB 711
Research Area: Dietary nutrients are known to have a profound influence on blood cell production and in the progression of cancer. Vitamins and amino acids participate as acceptors and donors of one-carbon metabolism and as cofactors or substrates of epigenetic regulators. Epigenetic dysregulation is a driver of hematopoietic malignancy, causing alterations in gene expression, chromatin or DNA methylation states, genomic stability and tumor heterogeneity.

My research interests are to understand how environmental factors, such as micronutrients, influence the activity of epigenetic regulators to control hematopoietic stem cell maintenance and transformation. The Ten-Eleven Translocation (TET) proteins (TET1-3) are Fe2+ and α-ketoglutarate-dependent dioxygenases that oxidize methylated cytosines in the genome, a key intermediate step in the process of DNA demethylation and transcriptional regulation. TET2 loss-of-function mutations are a driving event in hematopoietic malignancies, occurring in up to 30% of patients with myeloid malignancies and clonal hematopoiesis – a pre-malignant state seen in approximately 10% of healthy elderly individuals that increases their risk of progression to acute myeloid leukemia (AML). Using genetic models of reversible TET2 deficiency we have shown that restoring TET2 function can block aberrant hematopoietic stem cell self-renewal and leukemia progression.

Vitamin C is an essential dietary requirement for humans and acts as cofactor of TET enzymes by maintaining iron in the ferrous state. High-dose vitamin C treatment can mimic Tet2 restoration by increasing the activity of residual TET proteins in Tet2-deficient mouse models and in human AML cells. Targeted activation of TET2 function using high-dose vitamin C treatment could provide a safe and effective strategy to treat patients with TET2 mutations. These findings highlight the importance of the micronutrient environment in maintaining the activity of critical epigenetic regulators that drive and influence disease progression. Furthermore, targeting the epigenome via micronutrient availability represents a novel therapeutic approach to maintain normal blood cell production and to prevent and treat blood malignancies.

Publications: Cimmino L, Neel BG, Aifantis I. Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol. 2018 Sep;28(9):698-708.

Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, Ng V, Xia B, Witkowski MT, Mitchell-Flack M, Grillo I, Bakogianni S, Ndiaye-Lobry D, Martín MT, Guillamot M, Banh RS, Xu M, Figueroa ME, Dickins RA, Abdel-Wahab O, Park CY, Tsirigos A, Neel BG and Aifantis I. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. Sep 7;170(6):1079-1095, 2017.

Cimmino L, Aifantis I. Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev. Feb;42:1-7, 2017.

Cimmino L, Dawlaty MM, Ndiaye-Lobry D, Yap YS, Bakogianni S, Yu Y, Bhattacharyya S, Shaknovich R, Geng H, Lobry C, Mullenders J, King B, Trimarchi T, Aranda-Orgilles B, Liu C, Shen S, Verma AK, Jaenisch R & Aifantis I. Tet1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol. Jun;16(6):653-62, 2015.

Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I. Tet family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell. 9(3) 193-204, 2011.