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Rebekka Schneider-Kramann

About the research

Schneider Lab:
Rebekka K. Schneider, MD (Principal Investigator, Assistant Professor)

Research focus and projects

1. Extrinsic and intrinsic mechanism in the clonal advantage and erythroid differentiation defect of the hematopoeietic stem cell in del(5q) MDS

Del(5q) myelodysplastic syndrome (MDS) is a clonal disorder of hematopoiesis arising in a hematopoietic stem cell (HSC). In this disease, HSC acquire a deletion of one copy of the long arm of chromosome 5 (i.e. haploinsufficiency of 5q). During the course of the disease, 5q haploinsufficient HSC gain a clonal advantage in the bone marrow resulting in out-competition of normal hematopoiesis. Eventually, these cells can then undergo leukemic transformation. Therefore, del(5q) MDS serves as an excellent model for the study of both malignant hematopoiesis and oncogenesis more broadly.

Our previous studies have shown that the gene dosage effect of haploinsufficiency can be targeted therapeutically, demonstrating an approach for targeting of heterozygous deletions in cancer. Csnk1a1 haploinsufficiency conferred increased intrinsic self-renewal of HSC and nuclear  -Catenin accumulation. In striking contrast, Csnk1a1 homozygous inactivation is not tolerated in HSC due to activation of p53 (Schneider et al. Cancer Cell 2014).

Our recent data further identified an unexpected link between haploinsufficiency for genes on Chromosome 5, activation of the innate immune system and myelodysplasia. The activation of the innate immune system was associated with consecutive inflammation in the bone marrow niche and senescence of hematopoietic cells. Our findings underscore a molecular link between the genetic abnormalities in MDS patients, activation of the innate immune system, and ineffective hematopoiesis that characterizes the disease (Schneider et al. Nature Medicine 2016).

In ongoing work we aim to dissect the role of Wnt signaling as an intrinsic mechanism and inflammation as an extrinsic mechanism in the pathogenesis of del(5q) MDS.

2. Del(5q) MDS as a ribosomopathy
Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. The 5q? syndrome, a subtype of myelodysplastic syndrome (MDS), is caused by a somatically acquired deletion of the long arm of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and a distinct erythroid phenotype. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.

We have generated a novel murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect resulting in age- and erythroid stress-dependent progressive anaemia, (Schneider et al., Nature Medicine 2016). Protein synthesis was significantly reduced in Rps14 haploinsufficient hematopoietic stem cells (HSCs) and particularly in erythroid progenitor cells relative to wild-type cells. As assessed by quantitative proteomics, Rps14 haploinsufficient erythroblasts expressed higher levels of proteins involved in innate immune signalling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9 (alarmins). S100a8 is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells (phenocopy), and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. This data links Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.

In ongoing work we aim to get a better molecular and cellular understanding of the effects of ribosomal haploinsufficiency on protein translation, S100A8/S100A9 induction and p53 to identify novel therapeutic opportunities for the treatment of the 5q- syndrome, MDS more broadly and congenital bone marrow failure syndromes with ribosomal haploinsufficiency

3. Identifying the cellular drivers of bone marrow fibrosis
Our recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in bone marrow (BM) fibrosis, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis (Schneider et al. Cell Stem Cell, in press). These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target.

We now aim to dissect the hematopoesis-stroma interactions in bone marrow fibrosis and to analyze how this interaction affects the progression of BM fibrosis and the selection of malignant hematopoietic clones in myeloproliferative neoplasms over normal hematopoiesis (self-reinforcing niche).