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 this next year, they plan to capture and sequence more human AML patient single cells (approximately 24 additional patient samples, yielding approximately 2,400 additional cells). In addition, the group is studying mechanisms of leukemiagenesis in a p53 mutant model of leukemia progression. They have 120 of these samples to be submitted for bulk RNA sequencing. They are also studying the effects of alternative splicing on leukemia self renewal. 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 Llorens
Daniel Chang
Dongmei Chen
Yoonkyu Lee
Danielle Maeser
Sue Rathe
Dr. Zohar Sachs
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