Desperately seeking a home marrow niche for T-cell acute lymphoblastic leukaemia

Calvo, Julien; Fahy, Lucine; Uzan, Benjamin; Pflumio, Françoise

doi:10.1016/j.jbior.2019.100640

Cited by 12 publications

(11 citation statements)

References 69 publications

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“…Other environmental cues produced by stromal cells in the leukemic niche also partake in the onset and maintenance of T-ALL [3,64]. The OP9-DL1 co-culture system has emerged as a valuable in vitro model for T-cell development but also to study the relevance of extracellular signals for leukemia cell survival [65,66].…”

Section: Discussionmentioning

confidence: 99%

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.

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Section: Discussionmentioning

confidence: 99%

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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“…45 Additional heterogeneity of structural and metabolic differences occur at different sites in the body including alterations with aging. 46,47 Integrating imaging approaches and genetic and transcriptomic sequencing analyses 48 at single-cell resolution with molecular interactome maps in normal HSC have revealed dynamic relationships. 33,34,49,50 Taken together, specific differences in the localization of leukemic cells upon engraftment and chemotherapy exist between BCP-and T-ALL, suggesting the existence of favorable predilection sites in the bone marrow microenvironment.…”

Section: Imaging Of Notch-induced Murine T-all and T-all Pdx Revealed...mentioning

confidence: 99%

B- and T-cell acute lymphoblastic leukemias evade chemotherapy at distinct sites in the bone marrow

Barz¹,

Behrmann²,

Capron³

et al. 2022

haematol

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Persistence of residual disease after induction chemotherapy is a strong predictor of relapse in acute lymphoblastic leukemia (ALL). The bone marrow microenvironment may support treatment escape. Using 3D fluorescence imaging of 10 primary ALL xenografts we identify sites of predilection in the bone marrow for resistance to induction with dexamethasone, vincristine and doxorubicin. We detect B-cell precursor ALL cells predominantly in the perisinusoidal space at early engraftment and after chemotherapy. The spatial distribution of T-ALL cells was more widespread with contacts to endosteum, nestin+ pericytes and sinusoids. Dispersion of T-ALL cells in the bone marrow increased under chemotherapeutic pressure. A subset of slowly dividing ALL cells was transiently detected upon short-term chemotherapy, but not at residual disease after chemotherapy, challenging the notion that ALL cells escape treatment by direct induction of a dormant state in the niche. These lineage-dependent differences point to niche interactions that may be more specifically exploitable to improve treatment.

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“…FGFs are abundantly expressed by bone marrow stromal cells and secreted in exosomes, which are then endocytosed by leukemia cells, contributing to resistance to tyrosine kinase inhibitors (TKIs) [ 31 ]. Although T-ALL originates in the thymus, FGFR signaling might create a leukemia-protective microenvironment for T-ALL cells infiltrating the bone marrow niche, similarly to the effects of FGFR signaling demonstrated for AML cells [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Small RNA-Seq Reveals Similar miRNA Transcriptome in Children and Young Adults with T-ALL and Indicates miR-143-3p as Novel Candidate Tumor Suppressor in This Leukemia

Dawidowska

Maćkowska-Maślak

Drobna-Śledzińska

et al. 2022

IJMS

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We aimed to identify miRNAs and pathways specifically deregulated in adolescent and young adult (AYA) T-ALL patients. Small RNA-seq showed no major differences between AYA and pediatric T-ALL, but it revealed downregulation of miR-143-3p in T-ALL patients. Prediction algorithms identified several known and putative oncogenes targeted by this miRNA, including KRAS, FGF1, and FGF9. Pathway analysis indicated signaling pathways related to cell growth and proliferation, including FGFR signaling and PI3K-AKT signaling, with the majority of genes overrepresented in these pathways being predicted targets of hsa-miR-143-3p. By luciferase reporter assays, we validated direct interactions of this miRNA with KRAS, FGF1 and FGF9. In cell proliferation assays, we showed reduction of cell growth upon miR-143-3p overexpression in two T-ALL cell lines. Our study is the first description of the miRNA transcriptome in AYA T-ALL patients and the first report on tumor suppressor potential of miR-143-3p in T-ALL. Downregulation of this miRNA in T-ALL patients might contribute to enhanced growth and viability of leukemic cells. We also discuss the potential role of miR-143-3p in FGFR signaling. Although this requires more extensive validation, it might be an interesting direction, since FGFR inhibition proved promising in preclinical studies in various cancers.

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Desperately seeking a home marrow niche for T-cell acute lymphoblastic leukaemia

Cited by 12 publications

References 69 publications

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

B- and T-cell acute lymphoblastic leukemias evade chemotherapy at distinct sites in the bone marrow

Small RNA-Seq Reveals Similar miRNA Transcriptome in Children and Young Adults with T-ALL and Indicates miR-143-3p as Novel Candidate Tumor Suppressor in This Leukemia

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