Project

Towards Personalized Therapy of Hematopoietic Diseases: ldentification of New Therapeutic Targets against Hematopoietic Malignancies by Proteomic Analysis of (Pre)Leukemic Stem Cells

Short Summary

Acute myeloid leukemia (AML) and myeloproliferative neoplasia (MPN) are aggressive diseases of hematopoietic stem and progenitor cells with poor prognosis. Disease progression and relapse in AML are attributed to recently identified (pre)leukemic stem cells (preLSCs). PreLSCs survive induction chemotherapy in AML patients and can thus cause recurrences. Because preLSCs from AML patients are genetically very heterogeneous, they are best isolated from patients with more homogeneous preleukemic conditions such as MPN, which often evolve into AML. Whereas preLSCs have been analyzed on the genome level, the consequences of the genetic mutations for the cellular proteome are unknown at present. Yet, it is the protein expression, which potentially allows targeting of preLSCs in a directed fashion. Therefore, we have collected MPN and AML blood and bone marrow samples, isolated MPN/(pre)leukemic stem cells and developed a new methodology for broad-spectrum proteome analysis of preLSCs. Changes specific to MPN/(pre)leukemic stem cells are tested for correlation with disease progression. Potential target structures are validated functionally.

Goals

This study aims to identify new biomarkers for preLSCs as well as possible protein targets for potential eradication of preLSCs in myeloid neoplasms and thus contributes to the further development of personalized (precision) medicine in hemato-oncology.

Significance

MPN and especially AML patients often suffer from severe disease with poor prognosis and high morbidity/mortality. With currently poor chances for a cure, this project serves to identify new therapeutic targets and provides the potential for more effective and definitive leukemia treatments.

Background

In preparation for this study, we have developed a new proteomics workflow for the analysis of rare cell populations. The methodology has been validated in hematopoietic stem and progenitor cells from healthy donors and is now ready for analysis of MPN/(pre)leukemic stem cells. Clinical cell samples required for the study have been collected and viably frozen during the last five years. Neither for patients nor for healthy stem cell donors (controls) did further risks arise in addition to routine measures, which were carried out as part of their clinical care.

Transition Postdoc Fellowship Project

Co-Investigators

Prof. Dr. Ruedi Aebersold, PhD, ETHZ, University of Zurich
Prof. Dr. Markus Manz, MD, University and University Hospital of Zurich

Consortium

Status

Completed

2nd Call, TPdF