A photo of Lee Grimes.

H. Leighton "Lee" Grimes, PhD


  • Director, Cancer Pathology Program, Division of Experimental Hematology & Division of Pathology
  • Co-Leader, Program in Hematologic Malignancies of Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute
  • Professor, UC Department of Pediatrics

About

Biography

Determining the difference between important and unimportant DNA changes in childhood diseases can be tedious and difficult. The Grimes lab works to understand how normal hematopoiesis is programmed, and how diseases like marrow failure and leukemia change the transcriptional programming.

Dr. Grimes has a broad background in hematopoiesis, molecular biology and molecular oncology, including mouse modeling of hematopoiesis, myelopoiesis, marrow failure syndromes and leukemia.

He received a PhD in molecular pathology and immunology studying gene regulation with Maureen Goodenow (then at University of Florida). He then joined Philip Tsichlis (then at Fox Chase Cancer Center) when that lab was cloning novel genes activated by Moloney murine leukemia virus insertion mutagenesis (e.g., Akt, Tpl2).

Dr. Grimes participated in the identification of the Growth factor independent-1 (Gfi1) transcription factor, its DNA binding specificity, named the “SNAG” transcription repressor domain, and genetically linked this domain to Gfi1-directed biology.

The Grimes lab continues to focus on transcriptional integration of normal and malignant hematopoiesis.

With University of Washington colleague Marshall Horwitz, Dr. Grimes identified humans with mutations in Gfi1 who display severe congenital neutropenia (SCN) and non-immune chronic idiopathic neutropenia of adults (NI-CINA).

The Grimes lab has established multiple mouse models of human disease, including acute myeloid leukemia (AML), and more recently SCN. Their work has spanned both small molecule and RNA therapeutics.

In a 2016 study published in Cancer Discovery, they proved that DNMT3A haploinsufficiency could facilitate AML genesis.

The Grimes lab was one of the first labs to utilize deep scRNA-seq profiling to dissect homeostatic myeloid development and provide deep molecular insight into the process of differentiation. This work was published in Nature in 2016.

They went on to generate the first mouse models of human SCN using patient-derived mutations in the Gfi1 transcription factor. This work was published in Nature in 2020.

To determine the effects of SCN mutations, the team generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate-immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

The Grimes lab is actively harnessing both established and cutting-edge single-cell technologies to dissect the transcriptional and epigenetic programming of normal and malignant hematopoiesis. In collaboration with Nathan Salomonis here at Cincinnati Children’s, they develop biologically-centric informatics algorithms to process single-cell data, web portals to disseminate the work flows, and web browsers to make the data easily accessible to biologists.

Publications

Selected

Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Olsson, A; Venkatasubramanian, M; Chaudhri, VK; Aronow, BJ; Salomonis, N; Singh, H; Grimes, HL. Nature. 2016; 537:698-702.

Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice. Avellino, R; Mulet-Lazaro, R; Havermans, M; Hoogenboezem, R; Smeenk, L; Salomonis, N; Schneider, RK; Rombouts, E; Bindels, E; Grimes, L; et al. Blood Advances. 2022; 6:1406-1419.

GM-CSF Programs Hematopoietic Stem and Progenitor Cells During Candida albicans Vaccination for Protection Against Reinfection. Bono, C; Guerrero, P; Jordán-Pla, A; Erades, A; Salomonis, N; Grimes, HL; Gil, ML; Yáñez, A. Frontiers in Immunology. 2021; 12.

Why Single-Cell Sequencing Has Promise in MDS. Zhang, X; Grimes, HL. Frontiers in Oncology. 2021; 11.

Divisional Memory Drives Hematopoietic Stem Cell Functional Diversity. Bartram, J; Song, BA; Xu, J; Salomonis, N; Grimes, HL; Filippi, M. Blood. 2021; 138:20-20.

scTriangulate: Decision-level integration of multimodal single-cell data. Li, G; Song, B; Grimes, HL; Prasath, S; Salomonis, N. 2021.

Isolation of primary immune cells from fibrotic skin, esophageal, and gut tissue. Steele, H; Song, B; Willicut, A; Grimes, HL; Herro, R. Journal of Immunological Methods. 2021; 497.

Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function. Basu, J; Reis, BS; Peri, S; Zha, J; Hua, X; Ge, L; Ferchen, K; Nicolas, E; Czyzewicz, P; Cai, KQ; et al. Nature Immunology. 2021; 22:969-982.

3127 – COMPREHENSIVE ATLAS OF MIXED-LINEAGE STATES. Song, BA; Grimes, HL; Salomonis, N; Ferchen, K; Zhang, X. Experimental Hematology. 2021; 100.

Inflammation rapidly recruits mammalian GMP and MDP from bone marrow into regional lymphatics. Serrano-Lopez, J; Hegde, S; Kumar, S; Serrano, J; Fang, J; Wellendorf, AM; Roche, PA; Rangel, Y; Carrington, LJ; Geiger, H; et al. eLife. 2021; 10.

From the Blog


Single Cell Approach Reveals Impact of Disease-Causing Gene Mutations
Big Data and Analytics

Single Cell Approach Reveals Impact of Disease-Causing Gene Mutations

H. Leighton "Lee" Grimes, PhD, Nathan Salomonis, PhD3/22/2021

Perspective on Single-Cell Analyses of Genetic Disease Models
Tools for Science

Perspective on Single-Cell Analyses of Genetic Disease Models

H. Leighton "Lee" Grimes, PhD4/23/2020

Finding Genetic Ripple Effects in a Single-Cell Environment
Genomics and Development

Finding Genetic Ripple Effects in a Single-Cell Environment

H. Leighton "Lee" Grimes, PhD, Nathan Salomonis, PhD4/22/2020

Bold Findings About Blood Cell Formation Stir the Scientific Pot
Autoimmune Disorders

Bold Findings About Blood Cell Formation Stir the Scientific Pot

H. Leighton "Lee" Grimes, PhD, Nathan Salomonis, PhD6/30/2019