Abstract
SummaryThe bone-marrow (BM) niche is the spatial environment composed by a network of multiple stromal components regulating adult hematopoiesis. We use multi-omics and computational tools to analyze multiple BM environmental compartments and decipher their mutual interactions in the context of acute myeloid leukemia (AML) xenografts. Under homeostatic conditions, we find a considerable overlap between niche populations identified using current markers. Our analysis defines eight functional clusters of genes informing on the cellular identity and function of the different subpopulations and pointing at specific stromal interrelationships. We describe how these transcriptomic profiles change during human AML development and, by using a proximity-based molecular approach, we identify early disease onset deregulated genes in the mesenchymal compartment. Finally, we analyze the BM proteomic secretome in the presence of AML and integrate it with the transcriptome to predict signaling nodes involved in niche alteration in AML.
Highlights
Hematopoietic stem cells (HSCs) reside in a unique microenvironment referred to as the ‘‘niche,’’ which regulates the balance between self-renewal and differentiation of the hematopoietic stem compartment
We observed a certain degree of heterogeneity among acute myeloid leukemia (AML) samples, possibly linked to genetic diversity in our cohort (Figure 5B; Table 1), we identified a large common secretome signature within the AML cohort (Tables S4 and S5)
We focused our attention on the top commonly deregulated proteins and processes and validated their translational impact by comparing our dataset to recently published proteomics data retrieved from healthy donors and AML patients, as well as to a large cohort of patientderived transcriptomic dataset (Bagger et al, 2016; Celik et al, 2020)
Summary
Hematopoietic stem cells (HSCs) reside in a unique microenvironment referred to as the ‘‘niche,’’ which regulates the balance between self-renewal and differentiation of the hematopoietic stem compartment. To dictate HSC cell fate have been identified: the arteriolar niches (Ding et al, 2012), composed mainly of arteriole-associated sympathetic nerve fibers, Nestinhigh (Mendez-Ferrer et al, 2008) and/or Ng2+ cells (Yamazaki et al, 2011; Katayama et al, 2006), and the sinusoidal niches, where sinusoid-associated cxcl12-abundant reticular (CAR) cells (Omatsu et al, 2010), Nestinlow Lepr+ cells are located (Morrison and Scadden, 2014; Boulais and Frenette, 2015) These distinct vascular beds have a specific spatial distribution relative to the bone (Sivaraj and Adams, 2016) and have been shown to differentially regulate hematopoiesis and osteogenesis (Itkin et al, 2016; Langen et al, 2017; Chen et al, 2019)
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