GSE118964
Progression of progenitor B cell leukemia is associated with alterations of the bone marrow micro-environment
Many of the clinical manifestations of B-lymphoid leukemia is a consequence of disrupted formation of normal blood cells. Upon diagnosis. the disease has often progressed into a state with a dramatic dominance of leukemic cells in the BM making it difficult to understand the environmental changes underlying the disruption in blood cell formation. To investigate this process in more detail we have explored pre-clinical stages of leukemia in a mouse model based on transplantation of B-ALL cells from  mice trans-heterozygote for mutations in the Ebf1 and Pax5 genes to non-conditioned hosts. This revealed that while the recipient HSC compartment was relatively intact, the presence of erythroid progenitors and in more advanced disease, lymphoid progenitors was reduced. Progression of disease was also reflected in changes of the cellular composition of non hematopoietic compartments as well as changes in gene expression patterns in specific cellular subpopulations. This included increased expression of the cytokine Il7 in the mature stroma cell compartments. The relevance for Il7 in tumor progression was evident from the finding that leukemia development was delayed when tumor cells were transplanted to Il7 deficient mice. Our data suggest that progressive development of B-ALL primarily target the production of normal progenitor cells and that the micro-environment undergo changes that can be predicted to result in a more permissive environment for tumor growth. Overall design: For short term transplantations ProB cells were sorted from lymph nodes of sick mice as Lin-CD19+IgM+igD-CD43+Kit+. 100.000 cells were iv-injected to each recipient. Mice were euthanized at indicated time points and organs harvested. As controls, for each experiment setup, four animals were injected with PBS/iFCS. RNA-seq was performed on primary bone marrow and lymph node derived ProB cells from leukemic Pax5+/-Ebf1+/- mice and Wt mice, as well as on non hematopoietic bone marrow stroma cells. Data analysis was performed by alignment to mouse reference genome (mm10 /GRCm38) and mapped with STAR  (Dobin et al, Bioinformatics, 2013)  followed by analysis by DESeq2 in R.