Multi-omic profiling of the leukemic microenvironment shows bone marrow interstitial fluid is distinct from peripheral blood plasma

Abstract

Background The bone marrow is the place of hematopoiesis with a microenvironment that supports lifelong maintenance of stem cells and high proliferation. It is not surprising that this environment is also favourable for malignant cells emerging in the bone marrow or metastasizing to it. While the cellular composition of the bone marrow microenvironment has been extensively studied, the extracellular matrix and interstitial fluid components have received little attention. Since the sinusoids connect the bone marrow interstitial fluid to the circulation, it is often considered to have the same composition as peripheral blood plasma. Stark differences in the cellular composition of the bone marrow and peripheral blood with different secretory capacities would however suggest profound differences. Methods In this study we set out to better define if and how the bone marrow interstitial fluid (BMIF) compares to the peripheral blood plasma (PBP) and how both are remodeled during chemotherapy. We applied a multi-omic strategy to quantify the metabolite, lipid and protein components as well as the proteolytic modification of proteins to gain a comprehensive understanding of the two compartments. Results We found that the bone marrow interstitial fluid is clearly distinct from peripheral blood plasma, both during active pediatric acute lymphoblastic leukemia and following induction chemotherapy. Either compartment was shaped differently by active leukemia, with the bone marrow interstitial fluid being rich in extracellular vesicle components and showing protease dysregulation while the peripheral blood plasma showed elevation of immune regulatory proteins. Following chemotherapy, the BMIF showed signs of cellular remodeling and impaired innate immune activation while the peripheral blood plasma was characterized by restored lipid homeostasis. Conclusion This study provides a comprehensive examination of the fluid portion of the acute lymphoblastic leukemia microenvironment and finds the contribution of either microenvironment to tumourigenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s40164-022-00310-0.

De Novo Cleaning of Chimeric MS/MS Spectra for LC-MS/MS-Based Metabolomics

“…Using data resampling, we also investigated the impact of sample size in a metabolomics study and found that having 5 samples in a metabolomics study is enough to purify half of the MS/MS spectra and effectively improve spectra quality (Text S7). , It should also be noted that the prediction performance of the trained XGBoost model might be reduced for metabolomics data generated in different LC/MS instruments. In particular, the intensity ratio RSDs used for prediction is instrument-dependent.…”

Integrating molecular pathway with genome-wide association data for causality identification in breast cancer

“…In order to mitigate the presence of batch effects across distinct GEO datasets, we conducted batch correction on the amalgamated gene expression matrix. Subsequently, the efficacy of this correction was assessed through Principal component analysis (PCA) [ 17 ]. PCA is a method of statistics that employs orthogonal transformation to change possibly correlated variables sets into a linearly independent variables sets.…”