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The bone marrow niche regulates redox and energy balance in leukemia stem cells

ABSTRACT: The Cxcr4-Cxcl12 axis has been postulated as a critical pathway dictating leukemia stem cell (LSCs) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of Cxcl12 in the AML microenvironment and the mechanism by which Cxcl12 exert its protective role in AML in vivo remain unresolved. We have evaluated the functional role of Cxcl12 secreted by early mesenchymal stromal cells (MSCs) and osteolineage committed cells in acute myeloid leukemia (AML) maintenance in vivo. Our results demonstrate that early MSCs, in contrast to committed osteoblasts, are integral part of the MLL::AF9 derived AML niche and control LSCs maintenance through Cxcl12 secretion. Cxcl12 from MSCs regulates the oxidative state of LSCs and promotes energy metabolism. Furthermore, the protective role of the niche through the activation of the CXCL12-CXCR4 axis, may also represent a biological hallmark in human pediatric and adult AML, hence, reinforcing the notion that targeting the MSCs-derived CXCL12 may help eradicate leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE189928 | GEO | 2022/11/01

REPOSITORIES: GEO

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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by infiltration of the bone marrow and other sites with transformed T cell progenitors. The role of tissue microenvironments in the pathogenesis of T-ALL or any other type of acute leukemia is little understood. In delineating interactions between T-ALL cells and their environment, we initially found that T-ALL cells express high surface levels of the chemokine receptor CXCR4. Intravital imaging of an intact tibia revealed T-ALL cells in direct contact with bone marrow stromal cells producing the CXCR4 ligand, CXCL12. Genetic targeting of CXCR4 on T-ALL cells resulted in a marked reduction of leukemia burden and prolonged disease remission, and disruption of the CXCL12/CXCR4 axis using small molecule inhibitors prevented T-ALL progression in a primary xenograft model. Finally, we were able to show that CXCR4 inhibition significantly decreased expression of Myc and its target genes. Myc expression is a key regulator of T-ALL leukemia initiating cell (LIC) activity, suggesting that CXCR4 inhibition can suppress LIC activity by silencing the Myc response in T-ALL cells. Our data suggest that targeting of CXCL12/CXCR4 signaling could be a powerful new tool for combating T-ALL, a disease with no current targeted therapies. Mouse T-ALL cells were treated ex vivo with Cxcr4 inhibitor AMD3100 or vehicle control. Additionally, mouse T-ALL primary tumors were isolated from control (Cxcr4+/+) or knockout (Cxcr4-/-) animals. Total RNA was extracted from samples using the RNeasy Plus Mini Kit (Qiagen). Samples were then subject to PolyA selection using oligo-dT beads (Life Technologies, Carlsbad, CA) according to the manufacturer's instructions. The resulting RNA samples were then used as input for library construction using the dUTP method as described by Parkhomchuck et al., 2009. RNA libraries were then sequenced on the Illumina HiSeq 2500 using 50bp single-end reads.

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The bone marrow niche regulates redox and energy balance in leukemia stem cells

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