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. The Shlush lab aims to enhance myeloid malignancies outcomes through early diagnosis and treatment.

Challenges

The lab faces three significant 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.

Specific Aims

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

Aim 1

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

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

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

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

1. Created the first reference map of peripheral blood (PB) HSPCs from 150 healthy individuals.
2. Developed a dynamic 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.