Understanding Diagnosing and Early intervention in the Myeloid malignancy Continuum

Introduction

As humans age, Hematopoietic Stem and Progenitor Cells (HSPCs) accumulate preleukemic mutations (pLMs), forming preleukemic HSPCs (preL-HSPCs) and leading to clonal hematopoiesis (CH). While the link between CH and myeloid malignancies is established, predicting progression remains elusive.

Objectives

The Shlush lab aims to enhance myeloid malignancies outcomes through early diagnosis and treatment. Still, it faces three gaps:

1. Lacking advanced tools for diagnosis/risk stratification beyond mutations.
2. Insufficient understanding of pLMs functional consequences.
3. Absence of targeted therapies against pLMs.

Proposed Specific Aims

To address these challenges, our proposed specific aims are as follows:

Aim 1: Diagnostic Tool Development

Develop a novel diagnostic tool for myeloid leukemia using single-cell RNA sequencing (scRNAseq) of peripheral blood HSPCs from 1300 patients and replace bone marrow (BM) analysis in the future. Such a cohort will allow the discovery of novel mechanisms in leukemia and improved diagnostics.

Aim 2: In Vitro Assay Creation

Create an in vitro assay to explore molecular and functional consequences of human pLMs at the single-cell level, considering self-renewal and changing microenvironments.

Aim 3: Drug Identification

Identify drugs targeting human preleukemic HSPCs through a high-throughput drug screen of human preL-HSPCs. This novel approach aims to pave the way for targeted early interventions.

Progress Made

To make these goals feasible, the Shlush lab made three major steps forward:

1. Created the first reference map of peripheral blood (PB) HSPCs from 150 healthy individuals.
2. Developed a dynamics bone marrow in a dish allowing the study of human preL-HSPCs.
3. Developed the apoptosis score for detecting apoptosis in a small number of preL-HSPCs.