Department of Cell Biology

Dr. Satish Nandakumar, Ph. D. - Research Interest

Satish  


Assistant Professor, Department of Cell Biology

Ullmann Bldg., Room 915
718.430.2246
E-mail:
satish.nandakumar@einsteinmed.org

Research Interest 
Selected Publications 
Biosketch 
  

   Genetics of Blood Cancer Predisposition

Our laboratory is interested in understanding how inherited genetic variants contribute to hematologic malignancy. Myeloid malignancies are caused by acquired somatic mutations or chromosomal aberrations that result in dysregulation of cancer driver genes. These somatic driver mutations occur more frequently on a background of particular inherited germline variants. We are leveraging genome- wide association studies (GWAS) to prioritize germline genetic variants and identify mechanisms predisposing to myeloid malignancies and pre-leukemic conditions such as clonal hematopoiesis. Using CRISPR/Cas9 approaches and high-throughput screens in human hematopoietic stem and progenitor cells (HSPCs) and engineered mouse models, we are studying the impact of such genetic risk variants on hematopoiesis.

Role of hematopoietic stem cell (HSC) expansion in myeloid malignancy risk
Our recent work has uncovered a previously unappreciated mechanism for inherited risk of myeloid malignancies involving modulation of HSC function and self-renewal (Bao et al., Nature 2020; Bick et al., Nature 2020). We showed that non-coding germline variants identified from GWAS on myeloproliferative neoplasms and clonal hematopoiesis, influenced hematopoietic enhancers resulting in expansion of phenotypic human HSCs. We are currently developing murine models carrying germline deletions/point mutations of syntenic murine enhancers. Using these models, we will examine how modulating HSC pool size may predispose to myeloid malignancies.

Interactions between germline variants and somatic mutations underlying clonal hematopoiesis. Clonal hematopoiesis is an age-related premalignant condition characterized by expansion of blood cell clones carrying somatic mutations. GWAS have identified several genetic loci that predispose to clonal hematopoiesis, but underlying mechanisms remain unknown. In this project, we are examining functional interactions between GWAS nominated germline variants and common somatic mutations observed in clonal hematopoiesis. We are engineering human HSPCs using CRISPR/Cas9 to model both germline and somatic variants and examine clonal expansion using in vitro and in vivo assays.

High throughput approaches to systematically connect non-coding GWAS variants to genes regulating HSCs. The high prevalence of non-coding genetic variants presents a major challenge to GWAS functional validation studies. We are developing two high-throughput approaches in human HSPCs that are independent and complementary to systematically examine non-coding variants impacting blood cells. 1) A lentiviral massively parallel reporter assay (LentiMPRA) that uses DNA barcodes to quantify reporter activity of non-coding regions at high throughput in human HSPCs (Ulirsch et al., Cell 2016). 2) A pooled CRISPR/Cas9 screen to endogenously disrupt/ delete GWAS nominated putative enhancers in human HSPCs. We will apply these approaches to systematically identify the affected enhancers and genes at GWAS loci associated with clonal hematopoiesis and test effects of genetic variants on HSC function.

 
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