Abstract
The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or nullgenetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype.
Highlights
acute myeloid leukemia (AML) is a heterogeneous hematological disorder characterized by the accumulation of hematopoietic progenitor cells with acquired somatic genetic alterations
For each of the 5 conditions (4 groups corresponding to 4 types of AML, plus 1 group corresponding to control healthy mice), bone marrow was harvested from 5 mice and pooled, an accepted practice for gene expression profiling (GEP) [10]
After averaging duplicate results and subtracting log2-transformed data for AML-exposed bone marrow (BM)-MSC by data for control bone marrow mesenchymal stromal cells (BMMSC) harvested on the same day, samples for MLL/ ENL+FLT3-ITD genotypes (Trp53 wt and Trp53 -/-) were nearest neighbors, and clustered next to the data for MLL/ENL leukemia cells (Figure 1A)
Summary
AML is a heterogeneous hematological disorder characterized by the accumulation of hematopoietic progenitor cells with acquired somatic genetic alterations. Such alterations affect normal mechanisms of selfrenewal, proliferation, and differentiation, and give the abnormal hematopoietic cells a growth/survival advantage over their normal counterparts. There is a large body of evidence indicating that the AML cell genotype underlies observed variations in the response of patients to chemotherapy; it is not surprising that leukemia cells can modify their BM microenvironment, and “educate it” to promote leukemia progression. Many studies support these findings [6,7,8], little is known about how genetic aberrations in tumor cells differentially impact the genetic and phenotypic changes in the tumor stroma. We show specific and common transcriptional changes in BM-MSC driven in vivo by leukemia cells harboring different genotypes
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