NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

Santos, Nuno; Ghezzo, Marinella N.; Silva, Ricardo C. da; Fernandes, Mónica T.

doi:10.3390/cancers2041838

Cited by 18 publications

(14 citation statements)

References 128 publications

(199 reference statements)

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“…Furthermore, our group has found that expression of the NF‐κB transcription factor RELB in non‐haematopoietic stromal cells contributes to the development of T‐ALL in a mouse model (dos Santos et al , ). RELB is a critical NF‐κB transcription factor that is activated following engagement of tumour necrosis factor receptor (TNFR) superfamily members, thus hinting that TNFR‐like signalling is implicated in T‐ALL (dos Santos et al , ).…”

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confidence: 99%

Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

et al. 2015

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SummaryLymphotoxin-mediated activation of the lymphotoxin-b receptor (LTbR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-a and LTb (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTa 1 b 2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTbR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr À/À mice present markedly less leukaemic thymocytes than agematched TEL-JAK2;Ltbr +/+ mice and interference with LTbR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTbR signalling in thymic stromal cells, thus promoting leukaemogenesis.

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Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

et al. 2015

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“…Taken together, these results suggest that Cyr61 has an important role in the resistance of ALL cells to Ara-C. Exogenous Cyr61 decreases Ara-C-induced apoptosis through the NF-κB signaling pathway. Several reports have observed constitutive NF-κB activation in ALL cells (29)(30)(31); this pathway could be activated by Cyr61, resulting in cellular proliferation and chemotherapy resistance in ovarian and breast cancer cells.…”

Section: Level Of Cyr61 Expression In All Cell Lines and All Bone Marmentioning

confidence: 96%

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

Cao

Song

et al. 2018

Int J Mol Med

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Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara-C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara-C-induced apoptosis of ALL cells, and its function was blocked by the use of the anti-Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl-2 in Ara-C-treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara-C partially via the NF-κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF-κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.

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“…Pathways related to the downregulated miRNAs were primarily related to TGF‐beta and NF‐κB signaling pathways and to apoptosis. NF‐κB signaling is a well‐known pathway involved in T‐ALL leukemogenesis due to pathway constitutive activation as well as through its antiapoptotic role . TGF‐beta signaling pathway is an important network involved on the control of hematopoiesis with a suppressing role in the growth of immune cells including T‐cells, and positive effects on T‐cell survival .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA expression profiles discriminate childhood T‐ from B‐acute lymphoblastic leukemia

Almeida¹,

Silva

Coutinho

et al. 2018

Hematological Oncology

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MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T‐ or B‐cell acute lymphoblastic leukemia (T‐ALL or B‐ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave‐one‐out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T‐ and B‐ALL, of which 10 (miR‐708‐5p, miR‐497‐5p, miR‐151a‐5p, miR‐151b, miR‐371b‐5p, miR‐455‐5p, miR‐195‐5p, miR‐1266‐5p, miR‐574‐5p, and miR‐425‐5p) were downregulated and six (miR‐450b‐5p, miR‐450a‐5p, miR‐542‐5p, miR‐424‐5p, miR‐629‐5p, and miR‐29c‐5p) were upregulated in childhood T‐ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B‐cell receptor signaling pathways for induced miRNAs and TGF‐beta signaling, apoptosis, and NF‐kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR‐29c‐5p on acute lymphoblastic leukemia subtypes and on disease prognosis.

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NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

Cited by 18 publications

References 128 publications

Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

MicroRNA expression profiles discriminate childhood T‐ from B‐acute lymphoblastic leukemia

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