scholarly journals NFAT transcription factors are essential and redundant actors for leukemia initiating potential in T-cell acute lymphoblastic leukemia

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254184
Author(s):  
Claire Catherinet ◽  
Diana Passaro ◽  
Stéphanie Gachet ◽  
Hind Medyouf ◽  
Anne Reynaud ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Calcineurin Inhibitors ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Functional Relevance ◽  
And Migration ◽  
Proliferation And Migration

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and anergy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in which Nfat genes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate that Nfat genes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.

scholarly journals NFAT Transcription Factors are Essential and Redundant Actors for Leukemia Initiating Potential in T-cell Acute Lymphoblastic Leukemia

2020 ◽  
Author(s):  
Claire Catherinet ◽  
Diana Passaro ◽  
Stéphanie Gachet ◽  
Hind Medyouf ◽  
Anne Reynaud ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Calcineurin Inhibitors ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Functional Relevance ◽  
And Migration ◽  
Proliferation And Migration

ABSTRACTT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and anergy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in which Nfat genes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate that Nfat genes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.

Role of the T-Cell Acute Lymphoblastic Leukemia Oncoprotein TLX1/HOX11 in Chromatin Dynamics and Gene Regulatory Networks.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 56-56
Author(s):  
Irene Riz ◽  
Kristin K. Baxter ◽  
Hyo Jung Lee ◽  
Reza Behnam ◽  
Teresa S. Hawley ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Dna Binding ◽  
Cell Fate ◽  
Malignant Transformation ◽  
Binding Sites ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Homeodomain proteins (homeoproteins) have long been recognized as powerful transcriptional regulators. Inappropriate expression of these transcription factors often leads to major developmental malformations or malignant transformation. The in vitro DNA binding sites of homeoproteins are short sequences that are widely distributed throughout the genome and some canonical binding sites have been shown to be functionally important at distances >20 kb away from the nearest transcription start site. In addition to DNA-binding activity, several homeoproteins have been demonstrated to interact with chromatin-modifying enzymes. For example, we and others have reported that the TLX1 homeoprotein of T-cell acute lymphoblastic leukemia (T-ALL) inhibits the PP1/PP2A serine/threonine phosphatases (I. Riz and R.G. Hawley, Oncogene 24: 5561–5575, 2005) and more recently have found that TLX1 modulates histone/transcription factor acetyltransferase CBP activity (I. Riz et al., Oncogene 26: 4115–4123, 2007). PP1/PP2A and CBP are complex molecular machines integrating diverse regulatory pathways that impact on cell survival, proliferation and differentiation outcomes. Organogenesis and malignant transformation - despite obvious differences - share a common requirement for high-order cooperativity of transcription factors and transcriptional cofactors in regulating the expression of multiple sets of genes executing cell fate shifts. Targeting key regulatory nodes in order to coordinately regulate multiple genes is a common strategy of virus induced cell-transformation: accordingly, PP1/PP2A and CBP are targeted by transforming viral proteins. The Groucho/TLE (transducin-like Enhancer-of-split) family of corepressors are another example of master regulators of cell fate; for instance, it was reported that triggering the MAPK signaling cascade inactivates TLE corepressors leading to coordinated derepression of a large number of genes involved in cell proliferation. We now demonstrate that TLX1 interferes with TLE1 repressive function. By streptavidin affinity-based precipitation of biotinylated recombinant TLX1 protein (TLX1 fused to a biotinylation peptide) we show in vivo interaction of TLX1 and TLE1 in several different cell types, including human T-ALL and neuroblastoma cells. Interaction of TLX1 with TLE1 occurs via an Engrailed homology 1 (Eh1)-like domain as documented by GST pull-down assays and laser scanning confocal microscopy. Transient transfection experiments indicate that TLX1 prevents TLE1-mediated repression of reporter genes. Furthermore, in the context of endogenous chromatin structure, TLX1 derepresses the bHLH transcription factor gene, ACSL1(HASH1), a well characterized target of the HES1/TLE1 repressor complex. The process requires direct interaction of TLX1 with TLE1 and binding of TLX1 to DNA, since a point mutation in the Eh1-like motif or deletion of the third helix of the TLX1 homeodomain abrogated the effect. Additional data to be presented suggest a long-range mechanism of transcriptional regulation by TLX1: we propose that “transcriptional activation” by TLX1 (and, by analogy, other homeoproteins that interact with TLE corepressors) results in part from the chaperoned redistribution of TLE corepressors from proximal promoter regions of target genes to distal chromatin regulatory sites.

scholarly journals The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4169-4173 ◽  
Author(s):  
Alejandro Gutierrez ◽  
Alex Kentsis ◽  
Takaomi Sanda ◽  
Linda Holmfeldt ◽  
Shann-Ching Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Molecular Subtypes ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Missense Mutations ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation.

scholarly journals T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1118
Author(s):  
Valentina Bardelli ◽  
Silvia Arniani ◽  
Valentina Pierini ◽  
Danika Di Giacomo ◽  
Tiziana Pierini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Lymphoblastic Leukemia ◽  
Protein Translation ◽  
Thymocyte Development ◽  
Ras Pathway ◽  
Cell Processes ◽  
Genetic Subgroup ◽  
Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

scholarly journals Lymphoblastic lymphoma: an immunophenotype study of 26 cases with comparison to T cell acute lymphoblastic leukemia

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 474-478 ◽  
Author(s):  
LM Weiss ◽  
JM Bindl ◽  
VJ Picozzi ◽  
MP Link ◽  
RA Warnke
Keyword(s):  
Monoclonal Antibodies ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
T Cell Differentiation ◽  
Cell Phenotype ◽  
Frozen Sections ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia

A series of 26 lymphoblastic lymphomas (LLs) and 13 T cell acute lymphoblastic leukemias (ALLs) were investigated using a battery of monoclonal antibodies applied to tissue frozen sections. Twenty-one of the LLs were of T lineage. All but one of the T cell LLs were of immature thymic phenotype, mostly corresponding to stage II cortical thymocyte development. The T cell LLs expressed Leu-1 in 100%, Leu-4 and Leu-9 in 95%, and Leu-5 in 85% of the cases. The high percentage of Leu-4 expression in this series is probably due to detection of cytoplasmic antigen with our methods. One LL was of pre-B or B cell and two cases were of common ALL phenotype. Two cases were of undefined phenotype, expressing markers of both B and T cell differentiation. Pediatric cases showed a greater tendency toward T cell phenotype than did adult cases. The cases of T cell ALL were immunophenotypically similar to the cases of T cell LL but showed a tendency toward a more immature phenotype.

scholarly journals MiR-7 Functions as a Tumor Suppressor by Targeting the Oncogenes TAL1 in T-Cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol 19 ◽  
pp. 153303382093413
Author(s):  
Hongbo Sun ◽  
Zhifu Zhang ◽  
Wei Luo ◽  
Junmin Liu ◽  
Ye Lou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Ectopic Expression ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
And Migration

Background: T-cell acute lymphoblastic leukemia is a hematologic malignancy characterized by T-cell proliferation, and in many cases, the ectopic expression of the oncogenic transcription factor T-cell acute lymphocytic leukemia protein 1 (TAL1). MicroRNA-7 has been shown to play a critical role in proliferation, migration, and treatment sensitivity in a diverse array of cancers. In this study, we sought to establish a novel link between microRNA-7 and T-cell acute lymphoblastic leukemia oncogenesis. Material and Method: To do so, we characterized gene expression of microRNA-7 as well as TAL1 in both T-cell acute lymphoblastic leukemia patient-derived tissue and cell lines, as well as performing functional luciferase assays to assess microRNA-7 binding to the TAL1 3′-untranslated region. We also performed growth, apoptosis, and migration experiments using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide, Annexin V, and transwell assays in the context of microRNA-7 overexpression. Results: We found that microRNA-7 expression is attenuated and inversely correlated with TAL1 expression in TAL1 + T-cell acute lymphoblastic leukemia cells. Additionally, microRNA-7 directly targets and suppresses TAL1 levels. Finally, microRNA-7 overexpression reduces growth, motility, and migration while inducing apoptosis in T-cell acute lymphoblastic leukemia cells, phenotypes that can be rescued by concomitant overexpression of TAL1. Conclusions: These results indicate that microRNA-7 functions as a potent tumor suppressor by inhibiting the oncogene TAL1 and suggest microRNA-7 could function as a prognostic biomarker and possible therapeutic in the clinical management of T-cell acute lymphoblastic leukemia.

scholarly journals Inactivation of LEF1 in T-cell acute lymphoblastic leukemia

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2845-2851 ◽  
Author(s):  
Alejandro Gutierrez ◽  
Takaomi Sanda ◽  
Wenxue Ma ◽  
Jianhua Zhang ◽  
Ruta Grebliunaite ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Molecular Pathogenesis ◽  
Comparative Genomic ◽  
Loss Of Function ◽  
Thymocyte Development ◽  
Hoxa Cluster ◽  
Pten Loss ◽  
Cell Acute Lymphoblastic Leukemia

Abstract To further unravel the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), we performed high-resolution array comparative genomic hybridization on diagnostic specimens from 47 children with T-ALL and identified monoallelic or biallelic LEF1 microdeletions in 11% (5 of 47) of these primary samples. An additional 7% (3 of 44) of the cases harbored nonsynonymous sequence alterations of LEF1, 2 of which produced premature stop codons. Gene expression microarrays showed increased expression of MYC and MYC targets in cases with LEF1 inactivation, as well as differentiation arrest at an early cortical stage of thymocyte development characterized by expression of CD1B, CD1E, and CD8, with absent CD34 expression. LEF1 inactivation was associated with a younger age at the time of T-ALL diagnosis, as well as activating NOTCH1 mutations, biallelic INK4a/ARF deletions, and PTEN loss-of-function mutations or activating mutations of PI3K or AKT genes. These cases generally lacked overexpression of the TAL1, HOX11, HOX11L2, or the HOXA cluster genes, which have been used to define separate molecular pathways leading to T-ALL. Our findings suggest that LEF1 inactivation is an important step in the molecular pathogenesis of T-ALL in a subset of young children.

scholarly journals Lymphoblastic lymphoma: an immunophenotype study of 26 cases with comparison to T cell acute lymphoblastic leukemia

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 474-478 ◽  
Author(s):  
LM Weiss ◽  
JM Bindl ◽  
VJ Picozzi ◽  
MP Link ◽  
RA Warnke
Keyword(s):  
Monoclonal Antibodies ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
T Cell Differentiation ◽  
Cell Phenotype ◽  
Frozen Sections ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia

Abstract A series of 26 lymphoblastic lymphomas (LLs) and 13 T cell acute lymphoblastic leukemias (ALLs) were investigated using a battery of monoclonal antibodies applied to tissue frozen sections. Twenty-one of the LLs were of T lineage. All but one of the T cell LLs were of immature thymic phenotype, mostly corresponding to stage II cortical thymocyte development. The T cell LLs expressed Leu-1 in 100%, Leu-4 and Leu-9 in 95%, and Leu-5 in 85% of the cases. The high percentage of Leu-4 expression in this series is probably due to detection of cytoplasmic antigen with our methods. One LL was of pre-B or B cell and two cases were of common ALL phenotype. Two cases were of undefined phenotype, expressing markers of both B and T cell differentiation. Pediatric cases showed a greater tendency toward T cell phenotype than did adult cases. The cases of T cell ALL were immunophenotypically similar to the cases of T cell LL but showed a tendency toward a more immature phenotype.

scholarly journals Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia

Leukemia ◽  
2016 ◽  
Vol 31 (8) ◽  
pp. 1798-1807 ◽  
Author(s):  
W S Liau ◽  
S H Tan ◽  
P C T Ngoc ◽  
C Q Wang ◽  
V Tergaonkar ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia
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