The non-coding RNA landscape of human hematopoiesis and leukemia

Abstract

Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs—such as LINC00173 in granulocytes—and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.

Transcriptional networks in acute myeloid leukemia

“…[248][249][250] Several bioinformatic studies have inferred roles for miRNAs in regulatory networks, 251 Long noncoding RNAs (lncRNAs, >200 bp) are emerging as key regulators of a growing number of normal biological process including cell differentiation and identity 253 and are differentially expressed in myelodysplastic syndrome and AML. [254][255][256][257] Recent studies have shown that lncRNAs are required for normal hematopoiesis where they regulate HSC activity and function, as well as myeloid and lymphoid differentiation. 256,258 Expression is cell type specific in human hematopoiesis, 256 and the expression of just four lncRNAs is sufficient to predict patient outcome across multiple AML cohorts.…”

“…[254][255][256][257] Recent studies have shown that lncRNAs are required for normal hematopoiesis where they regulate HSC activity and function, as well as myeloid and lymphoid differentiation. 256,258 Expression is cell type specific in human hematopoiesis, 256 and the expression of just four lncRNAs is sufficient to predict patient outcome across multiple AML cohorts. 255 Some lncRNAs, including those that originate from leukemia-associated genomic regions, function as oncogenic drivers in acute leukemia.…”

Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology

“…Hence, disruption of cellular processes in particular cell types may lead to phenotypic alterations or development of disease. This presumption in conjunction with the complexity of tissue-level (“bulk”) data has led to many cell-type-specific genomic studies, in which genomic features, such as gene expression levels, are assayed from isolated cell types in a group of individuals and studied in the context of a phenotype or condition of interest (e.g., 1–4 ).…”

Comprehensive microRNA expression profiling in cerebrospinal fluid distinguishes between neurological disease classes

“…P-values were calculated using the paired t-test for unequal variance after performing Levene's Test. I miR-142-3p expression in FACS-sorted hematopoietic cell populations (n = 5 per group; normalized data were obtained from GEO series GSE98791 [14]). HSC, haematopoietic stem cells; Ery, erythrocytes; Mega, megakaryocytes; Gran, granulocytes; Mono, monocytes; NK, natural killer cells; CD4T = CD4+ T-cells, CD8T = CD8+ T-cells.…”