Adaptive clonal hematopoiesis in bone marrow failure and leukemia predisposition

• Applicant: Dr. Felicia Miranda Katharina Andresen
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495452327

The hematopoietic system produces trillions of blood cells every day and therefore requires the continuous self-renewal and multilineage differentiation of pluripotent hematopoietic stem cells. Deregulation of these processes is thought to play a central role in the development of hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Germline genetic factors predisposing to leukemia development have been identified in a growing subset of children and adolescents with MDS or AML. Recognition of leukemia predisposition offers the opportunity for surveillance and preventative interventions. A recent study found that approximately 4% of young patients with MDS had unrecognized Shwachman Diamond Syndrome (SDS), which was associated with a poor prognosis. SDS is an inherited bone marrow failure syndrome and a disorder of ribosome biogenesis (also: ribosomopathy), which is caused by biallelic mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene in 90% of cases. The leading cause of mortality in SDS patients is MDS or leukemia. Germline leukemia predisposition syndromes have been associated with acquisition of somatic mutations at early ages, a process referred to as clonal hematopoiesis. The underlying germline defect results in reduced cellular fitness of hematopoietic stem cells. This germline defect is thought to exert strong selection pressure on hematopoietic stem cells to acquire somatic mutations that improve their competitive fitness specific to that context. A recent study from the Shimamura laboratory has investigated the role of clonal hematopoiesis and the genetic pathways that drive clonal hematopoiesis and leukemogenesis. Clinical and experimental data point to Eukaryotic Translation Initiation Factor 6 (EIF6) as playing a critical role in the pathogenesis of SDS. Acquisition of somatic mutations leading to EIF6 inactivation rescued the ribosomal stress of SBDS deficiency and thus might reduce the risk of leukemic transformation. The goal of this project is to elucidate the functional impact of adaptive clonal pathways on hematopoiesis and leukemic transformation in the context of bone marrow failure, in particular SDS. The long-term goal of this project is to influence compensatory signaling pathways to treat bone marrow failure while simultaneously preventing maladaptive pathways and reducing the risk of leukemia. SDS provides an ideal disease model to study these processes because SBDS mutations cause distinct compensatory and pre-leukemic somatic mutations.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Akiko Shimamura, Ph.D.