PhD candidate 'Unraveling Leukemic Transformation in DDX41-Mutant Acute Myeloid Leukemia'

Project description

Are you an ambitious and curious researcher eager to make a meaningful impact in cancer biology? We are seeking a highly motivated PhD candidate to join an exciting project aimed at understanding the mechanisms driving acute myeloid leukemia (AML) in individuals with germline DDX41 mutations.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by impaired differentiation and uncontrolled proliferation of hematopoietic stem and progenitor cells. In approximately 5-10% of the cases, inherited mutations in the RNA helicase gene DDX41 are found. Carriers have a lifetime leukemia risk of 50 to 75%.

Despite this strong genetic predisposition, the mechanisms underlying leukemic transformation remain poorly understood. DDX41-mutant AML presents a unique clinical paradox: disease onset typically occurs later in life and is accompanied by relatively few additional somatic mutations, suggesting alternative drivers beyond classical genetic events. It remains unknown why some carriers develop leukemia, whereas other do not. Understanding the underlying mechanisms may provide possibilities for clinical intervention and prevention of leukemia development.

In this KWF-sponsored PhD project, you will investigate the biological processes that trigger leukemic transformation in individuals carrying germline DDX41 mutations. You will explore both cell-intrinsic mechanisms (e.g., altered gene expression and differentiation programs) and cell-extrinsic factors (e.g., cytokines and circulating proteins) that may contribute to disease initiation and progression.

You will work at the forefront of translational hematology, combining patient-derived data with advanced molecular and computational techniques, including:

· Clonal evolution analysis to trace disease development in individuals with and without AML

· Plasma proteomics to identify systemic factors influencing transformation

· Stem cell modeling to study dysfunctional DDX41 in controlled settings

· Single-cell RNA sequencing to dissect cellular heterogeneity and gene expression changes

You will be appointed as a PhD candidate for a period of four years, starting around July 2026. During your PhD, you will design and perform laboratory experiments, conduct (bioinformatic) data analyses, write scientific manuscripts, and present your findings at lab meetings and (inter)national conferences. You will also contribute to student supervision and actively participate in team meetings.

Throughout the project, you will collaborate closely with an interdisciplinary team of molecular biologists and hematologists. Your PhD trajectory will culminate in the writing and defense of your PhD thesis.

Techniques and skills

During your PhD, you will gain hands-on experience with a wide range of molecular and cellular biology techniques, including:

· Culturing hematopoietic stem and progenitor cells to assess proliferation and differentiation

· DNA cloning and bacterial transformation

· Cell transfection, viral transduction, and CRISPR-Cas9-mediated gene editing

· (Quantitative) RT-PCR

· Flow cytometry

· Western blotting

· Next-generation sequencing techniques

· Mass spectrometry and associated bioinformatic analyses

This project offers an excellent opportunity to develop both experimental and computational skills in a dynamic and translational research environment.