Background
Childhood leukemia and lymphomas are diseases of white blood cell development. Human B and T lymphocytes arise from hematopoietic stem and progenitor cells (HSPCs) through a tightly choreographed developmental program in the bone marrow and thymus. Many leukemia-driving lesions occur at these early stages, and the affected cells escape the controls that normally limit their proliferation. The same developmental program, when disturbed by an inherited genetic defect, produces a different outcome resulting in recurrent infections, autoimmunity and a markedly increased risk of cancer. . Because each of these rare disorders is caused by a single, defined gene defect, they are also informative for the question of which developmental controls are lost in leukemia.
The earliest stages of human lymphocyte development, however, are almost inaccessible: patient material is scarce, and animal models do not fully recapitulate human biology. As a result, we still cannot explain why one child’s leukemia responds durably to a targeted drug while another’s relapses, and little is known about what our therapies do to the developing immune system a child needs to recover. This gap limits early diagnosis, risk stratification and the design of individualized treatment.
Our research
The questions that we address in the lab come from the ward: We reconstruct human lymphopoiesis outside the body to study it at its earliest, most inaccessible stages. By combining CRISPR gene editing of primary human hematopoietic stem and progenitor cells with artificial thymic (ATO) and bone marrow (ABMO) organoids, we generate developing T and B cells from an edited, isogenic background, independent of scarce primary patient material. This platform lets us introduce single or multiplexed genetic perturbations and follow their consequences for lymphocyte development at single-cell resolution, using paired transcriptome and antigen-receptor repertoire sequencing.
We use this approach to study two sides of the same biological problem.
- In pediatric leukemias and lymphomas, such as KMT2A-rearranged acute lymphoblastic leukemia, developing lymphocytes escape normal developmental control altogether.
- In children with rare inherited defects, for example in actin-regulatory proteins (immunoactinopathies), the same program is disturbed in a different way, causing immune dysregulation, autoimmunity and cancer predisposition.
Modeling both in the same ex vivo systems let us read out what each genetic lesion does to a developing lymphocyte, and embedding therapeutic testing, from menin inhibitors to targeted protein degraders, directly into these platforms allows drug effects to be assessed in the same developmental context.
Understanding leukemia/lymphoma initiation and testing inhibitors or protein degraders in a human developmental system, before or alongside a clinical trial, may help indicate which patients are most likely to benefit from a certain targeted treatment option, flag side effects early, and point to combinations worth testing. All results are intended to feed back into patient care as biomarkers, as candidate drug combinations, and as input into the design of early-phase trials.
We pursue three specific aims:
- Model normal and malignant human lymphopoiesis ex vivo, from hematopoietic stem cell to mature B and T cells.
- Determine how specific genetic lesions divert lymphocyte development.
- Evaluate targeted therapies, including protein degraders and small molecules, for their efficacy and impact on healthy lymphocyte development.
From the clinic to the clinic
Elisabeth Salzer is also a ward supervising oncologist at St. Anna Children’s Hospital, treating children and adolescents with all types of cancer, and European principal investigator of the APAL2020K trial, the first transatlantic pediatric menin inhibitor trial sponsored by the Princess Máxima Center for Pediatric Oncology in Utrecht. That collaboration, including a stay at the PMC as ITCC clinical fellow, is where she built her experience in designing and conducting phase 1/2 trials in children and adolescents with cancer. She currently co-coordinates the clinical side of the Precision Medicine Program (SUNRISE), which uses molecular profiling of tumors to identify treatment options for children with relapsed or refractory cancer and to match them to suitable trials or individualized treatment plans.
Selected Articles
About Elisabeth Salzer
Elisabeth Salzer studied Medicine at the Universities of Vienna and Lausanne. She completed her MD (2010) and PhD (2015) at the Medical University of Vienna, the latter at CeMM Research Center for Molecular Medicine, followed by clinical training in Pediatrics and Pediatric Hematology/Oncology at St. Anna Children’s Hospital. In 2022 she moved to the Leiden University Medical Center as Assistant Professor and Group Leader, where she built a research program combining CRISPR gene editing with ex vivo models of human lymphocyte development. During her time in the Netherlands, she obtained her license to practice medicine and completed a fellowship sponsored by the ITCC at the Princess Maxima Center for Pediatric Oncology. She obtained her Habilitation at the Medical University of Vienna in 2024 and now continues this work at St. Anna CCRI and St. Anna Children’s Hospital in Vienna.