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A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA437128PRJNA437512PRJNA437532

ORGANISM(S): Mus musculus

PROVIDER: GSE111613 | GEO | 2018/05/09

REPOSITORIES: GEO

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A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression.

Project description:In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13. Notably, reducing retinoic acid precursors from the diet or inhibiting RA-signaling through retinoid-antagonist therapy prolong survival by preventing dissemination of leukemia cells into lymphoid tissues. Furthermore, mouse and human leukemia cells could be distinguished from normal B-cells by their increased expression of Rarγ2 and RXRα, respectively. These findings establish a role for retinoids in murine CLL pathogenesis, and provide new therapeutic strategies to target the microenvironment and to control disease progression.

| S-EPMC5934403 | biostudies-literature

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [microarray]

Project description:In B-cell chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival and expansion. Using the Eμ-TCL1 mouse model, we demonstrate that leukemic cells induce the activation of retinoid acid synthesis and signaling in stromal cells of the lymphoid microenvironment.

2018-05-09 | GSE111470 | GEO

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [RNA-seq]

2018-05-09 | GSE111612 | GEO

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression

Project description:A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression

| PRJNA437512 | ENA

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [microarray]

Project description:A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [microarray]

| PRJNA437128 | ENA

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [RNA-seq]

Project description:A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [RNA-seq]

| PRJNA437532 | ENA

PRMT5 Promotes Progression of Chronic Lymphocytic Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-07 | GSE183432 | GEO

Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia.

Project description:Chronic lymphocytic leukemia (CLL) outgrowth depends on signals from the microenvironment. We have previously found that in vitro reconstitution of this microenvironment induces specific variant isoforms of the adhesion molecule CD44, which confer human CLL with high affinity to hyaluronan (HA). Here, we determined the in vivo contribution of standard CD44 and its variants to leukemic B-cell homing and proliferation in Tcl1 transgenic mice with a B-cell-specific CD44 deficiency. In these mice, leukemia onset was delayed and leukemic infiltration of spleen, liver, and lungs, but not of bone marrow, was decreased. Competitive transplantation revealed that CLL homing to spleen and bone marrow required functional CD44. Notably, enrichment of CD44v6 variants particularly in spleen enhanced CLL engraftment and proliferation, along with increased HA binding. We recapitulated CD44v6 induction in the human disease and revealed the involvement of MAPK and NF-κB signaling upon CD40 ligand and B-cell receptor stimulation by in vitro inhibition experiments and chromatin immunoprecipitation assays. The investigation of downstream signaling after CD44v6-HA engagement uncovered the activation of extracellular signal-regulated kinase and p65. Consequently, anti-CD44v6 treatment reduced leukemic cell proliferation in vitro in human and mouse, confirming the general nature of the findings. In summary, we propose a CD44-NF-κB-CD44v6 circuit in CLL, allowing tumor cells to gain HA binding capacity and supporting their proliferation.

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CD73 Promotes Chronic Lymphocytic Leukemia.

Project description:The ecto-nucleotidase CD73 is an important immune checkpoint in tumor immunity that cooperates with CD39 to hydrolyze pro-inflammatory extracellular ATP into immunosuppressive adenosine. While the role of CD73 in immune evasion of solid cancers is well established, its role in leukemia remains unclear. To investigate the role of CD73 in the pathogenesis of chronic lymphocytic leukemia (CLL), Eµ-TCL1 transgenic mice that spontaneously develop CLL were crossed with CD73-/- mice. Disease progression in peripheral blood and spleen, and CLL markers were evaluated by flow cytometry and survival was compared to CD73-proficient Eµ-TCL1 transgenic mice. We observed that CD73 deficiency significantly delayed CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ+ T cells and effector-memory CD8+ T cells. Neutralizing IFN-γ abrogated the survival advantage of CD73-deficient Eµ-TCL1 mice. Intriguingly, the beneficial effects of CD73 deletion were restricted to male mice. In females, CD73 deficiency was uniquely associated with the upregulation of CD39 in normal lymphocytes and sustained high PD-L1 expression on CLL cells. In vitro studies revealed that adenosine signaling via the A2a receptor enhanced PD-L1 expression on Eµ-TCL1-derived CLL cells, and a genomic analysis of human CLL samples found that PD-L1 correlated with adenosine signaling. Our study, thus, identified CD73 as a pro-leukemic immune checkpoint in CLL and uncovered a previously unknown sex bias for the CD73-adenosine pathway.

| S-EPMC9264813 | biostudies-literature

PRMT5 Promotes Progression of Chronic Lymphocytic Leukemia

Project description:PRMT5 Promotes Progression of Chronic Lymphocytic Leukemia

| PRJNA760770 | ENA