Biology subjects

Liesveld, J. L.

Publications and source records attributed to Liesveld, J. L..

4 recordsLinked to original sources

bioRxiv2025

Taurine Transporter SLC6A6 Expression Promotes Mesenchymal Stromal Cell Function

Mesenchymal stromal cell (MSC) differentiation is critical for the development, maintenance, and repair of bone tissue. This occurs within the bone marrow microenvironment, which consists of various stromal populations and structural components that support skeletal growth, repair and homeostasis. MSCs also promote self-renewal of hematopoietic stem cells and regulate their differentiation. Analysis of our own and publicly available single-cell RNA sequencing datasets of the murine non-immune bone and bone marrow indicates that Slc6a6 expression is enriched in MSCs. Slc6a6 encodes for an ion-dependent transporter of taurine (TauT). Although taurine supplements have been shown to mitigate the onset of bone defects in aged populations, the absence of TauT expression in osteolineage cells suggests that taurines effect on bone may be secondary to its function in other populations, such as MSCs. Using young TauT genetic loss-of-function murine models we find that TauT loss impacts MSC populations in vivo and impairs MSC osteogenic differentiation in vitro. This correlates with decreased bone mineral density and bone strength in young TauT knockout mice. Importantly, shRNA-based knockdown of SLC6A6 expression in primary human MSCs reduces osteogenic differentiation, indicating a key role of taurine uptake in human MSC function. Consistent with a decline in MSC function with TauT loss, we find that TauT null MSCs are unable to support self-renewal and expansion of co-cultured hematopoietic stem/progenitor populations. Mechanistically, our RNA-sequencing analysis identifies downregulation of Wnt/beta-catenin signaling in MSCs in the absence of TauT. These cells also show reduced oxidative phosphorylation, and increased ROS levels, indicating that impaired Wnt signaling and elevated oxidative stress may contribute to the observed defects in osteogenic differentiation capacity. Collectively, our data identify taurine uptake as a key regulator of mesenchymal stromal cell maintenance and osteogenic fate determination.

cell biology↗

bioRxiv2024

Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-{kappa}B activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

cancer biology↗

bioRxiv2024

Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia

Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified1-6, concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemias in vivo by downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax8, 9 to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.

cancer biology↗

bioRxiv2023

Myelodysplastic syndromes disable human CD271+VCAM1+CD146+ niches supporting normal hematopoietic stem/progenitor cells

Mesenchymal stem/stromal cells (MSCs) within the bone marrow microenvironment (BMME) support normal hematopoietic stem and progenitor cells (HSPCs). However, the heterogeneity of human MSCs has limited the understanding of their contribution to clonal dynamics and evolution to myelodysplastic syndromes (MDS). We combined three MSC cell surface markers, CD271, VCAM-1 (Vascular Cell Adhesion Molecule-1) and CD146, to isolate distinct subsets of human MSCs from bone marrow aspirates of healthy controls (Control BM). Based on transcriptional and functional analysis, CD271+CD106+CD146+ (NGFR+/VCAM1+/MCAM+/Lin-; NVML) cells display stem cell characteristics, are compatible with murine BM- derived Leptin receptor positive MSCs and provide superior support for normal HSPCs. MSC subsets from 17 patients with MDS demonstrated shared transcriptional changes in spite of mutational heterogeneity in the MDS clones, with loss of preferential support of normal HSPCs by MDS-derived NVML cells. Our data provide a new approach to dissect microenvironment-dependent mechanisms regulating clonal dynamics and progression to MDS.

cancer biology↗