Dr. Zohar Sachs

Medical School
Twin Cities
Project Title: 
Molecular Mechanisms of NRAS-Mediated Leukemia Stem Cell Self-Renewal

Acute myeloid leukemia (AML) is frequently fatal because patients who initially respond to chemotherapy eventually relapse. Leukemia stem cells (LSCs) recapitulate the disease by self-renewal. LSC self-renewal is therefore critical to relapse. NRASG12V is required for self-renewal in a murine AML model. These researchers are studying NRAS-mediated leukemia self-renewal using a transgenic mouse model of AML with an Mll-AF9 fusion and a tetracycline repressible, NRASG12V. The lab specializes in using gene expression profiling (primarily via RNA sequencing) to understand the mechanisms of self-renewal in this model of AML. They have used single cell RNA sequencing to examine the NRAS-activated stem-cell containing subpopulation of their mouse model and identify and characterize a novel, self renewing subgroup within this population. Currently, they are also capturing cells from primary human AML samples  (~100 cells) for single cell RNA sequencing to study this self-renewing subpopulation in primary human AML. In addition, they are studying mechanisms of leukemiagenesis in a p53 mutant model of leukemia progression. 120 of these samples will be submitted for bulk RNA sequencing for this project (125 cycle PE reads). The group is  also studying the effects of alternative splicing on leukemia self renewal. This project involves a small set (20) of samples for bulk RNA sequencing of sorted subpopulations that the researchers have identified in the mouse model (125 cycle PE reads). All these subprojects require large amounts of storage.

The group is finalizing findings from a single cell RNA sequencing analysis of their activated NRAS AML model for publication. They used single cell RNA sequencing to identify a novel subpopulation that is responsible for self-renewal in this model. These findings are critical to help define the mechanisms of self renewal, and therefore AML relapse, at the single cell level. Current work seeks to build on work in the murine model and study these mechanisms in human AML in order to identify therapeutic targets to prevent relapse in this fatal disease.

Project Investigators

Dr. Juan Abrahante Llorns
Daniel Chang
Dongmei Chen
Yoonkyu Lee
Sue Rathe
Dr. Zohar Sachs
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