Tumor Trp53 status and genotype affect the bone marrow microenvironment in acute myeloid leukemia

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.

Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support

“…As noted previously, MSC heterogeneity across AML subtypes is minimal [32,33,40]. Jacamo et al [48] found that despite differences in genotype and p53 status between four syngeneic primary AMLs, BM-MSCs from these mice shared certain transcription changes. Osteoblast maturation and differentiation were inhibited as were the mineralization and apoptosis of chondrocytes.…”

Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

“…Several in vitro studies have suggested functional alterations of BMSCs in AML, such as reduced proliferation ( Corradi et al., 2018 ; Desbourdes et al., 2017 ; Yehudai-Resheff et al., 2019 ), increased apoptosis ( Desbourdes et al., 2017 ), impaired differentiation and hematopoietic supporting activity in culture ( Doron et al., 2019 ; Geyh et al., 2016 ), inflammatory prolife ( Diaz de la Guardia et al., 2017 ; Forte et al., 2017 ; Jacamo et al., 2017 ; Kim et al., 2015 ; Kuett et al., 2015 ; Reikvam et al., 2015 ; Ruvolo et al., 2018 ; von der Heide et al., 2017 ), increased support of AML cells ( Ben-Batalla et al., 2013 ; Brenner et al., 2017 ; Kornblau et al., 2018 ; Wu et al., 2018 ), and AML protection from chemotherapy through increased Notch ( Takam Kamga et al., 2016 ) or Wnt ( Lane et al., 2011 ) signaling and apoptosis inhibition ( Carter et al., 2016 , 2019 ). However, whether these or other BMSC alterations play a critical role in AML in vivo has remained unclear.…”

The bone marrow microenvironment in health and disease at a glance

“…Modification of the BMM by malignant hematopoietic growth is a well-characterized phenomenon that affects the osteoblastic and vascular components of the BMM. However, this appears to be highly specific for oncogenic events in leukemia cells (Jacamo et al, 2017;Krause and Scadden, 2015). Vascular endothelial growth factor (VEGF) and other factors such as angiopoietin 2, which are secreted by leukemia cells, have been implicated in the proliferation of leukemia and endothelial cells in B-ALL (Veiga et al, 2006), AML (Hatfield et al, 2009) and CLL (Maffei et al, 2010).…”