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1.
Front Cell Dev Biol ; 9: 767510, 2021.
Article in English | MEDLINE | ID: mdl-34957100

ABSTRACT

Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.

2.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: mdl-33555272

ABSTRACT

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFß. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.


Subject(s)
Core Binding Factor Alpha 1 Subunit/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Animals , Cell Line, Tumor , Chemotaxis, Leukocyte , Child , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor beta Subunit/metabolism , Disease Progression , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Gene Rearrangement , Hematopoiesis , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , In Vitro Techniques , Mice , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Organelle Biogenesis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, CXCR4/metabolism , Signal Transduction
3.
Cancer Sci ; 110(6): 1931-1946, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30974024

ABSTRACT

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.


Subject(s)
Epigenesis, Genetic , Janus Kinases/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , STAT Transcription Factors/genetics , Suppressor of Cytokine Signaling Proteins/genetics , Animals , Cell Line , Cell Line, Tumor , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Disease Progression , Gene Expression Profiling , Humans , Janus Kinases/metabolism , Jurkat Cells , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , RNAi Therapeutics/methods , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/genetics , Suppressor of Cytokine Signaling Proteins/metabolism , Survival Analysis , Xenograft Model Antitumor Assays/methods
4.
Biomark Res ; 6: 27, 2018.
Article in English | MEDLINE | ID: mdl-30159143

ABSTRACT

For children and young adults with T-lineage acute lymphoblastic leukemia (T-ALL), event free survival following relapse is < 10%. We recently showed that rearrangements of the mixed lineage leukemia gene (KMT2A-R) are associated with induction failure and an inferior survival in T-ALL. Because there are currently no molecular features that inform treatment strategies in T-ALL, we hypothesized that transcriptional alterations related to KMT2A-R and MLLT10-R T-ALL could identify biologically relevant genes and signaling pathways for the development of targeted therapies for these groups of patients. We analyzed microarray data from a retrospective cohort of 100 T-ALL patients to identify novel targets for KMT2A (n = 12) or MLLT10 (n = 9) chimeras. We identified 330 probe sets that could discriminate between these groups, including novel targets, like RUNX2, TCF4 or MYO6. The results were further validated in two independent data sets and the functional networks were analyzed to identify pathways that may be of pathogenic or therapeutic relevance.

5.
SLAS Discov ; 23(7): 732-741, 2018 08.
Article in English | MEDLINE | ID: mdl-29746793

ABSTRACT

Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Drug Repositioning , Flow Cytometry , High-Throughput Screening Assays , Small Molecule Libraries , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Discovery/methods , Drug Repositioning/methods , Flow Cytometry/methods , Humans , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
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