scholarly journals TAL1 and LIM-Only Proteins Synergistically Induce Retinaldehyde Dehydrogenase 2 Expression in T-Cell Acute Lymphoblastic Leukemia by Acting as Cofactors for GATA3

1998 ◽  
Vol 18 (12) ◽  
pp. 6939-6950 ◽  
Author(s):  
Yuichi Ono ◽  
Norio Fukuhara ◽  
Osamu Yoshie
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Downstream Target ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Retinaldehyde Dehydrogenase

ABSTRACT Previously, we have shown that TAL1 and the LIM-only protein gene (LMO) are regularly coactivated in T-cell acute lymphoblastic leukemia (T-ALL). This observation is likely to relate to the findings that TAL1 and LMO are highly synergistic in T-cell tumorigenesis in double-transgenic mice. To understand the molecular mechanisms of functional synergy between TAL1 and LMO in tumorigenesis and transcriptional regulation, we tried to identify downstream target genes regulated by TAL1 and LMO by a subtractive PCR method. One of the isolated genes, that for retinaldehyde dehydrogenase 2 (RALDH2), was regularly expressed in most of the T-ALL cell lines that coexpressed TAL1 and LMO. Exogenously transfected TAL1 and LMO, but not either alone, inducedRALDH2 expression in a T-ALL cell line, HPB-ALL, not expressing endogeneous TAL1 or LMO. The RALDH2 transcripts in T-ALL were, however, mostly initiated within the second intron. Promoter analysis revealed that a GATA site in a cryptic promoter in the second intron was essential and sufficient for the TAL1- and LMO-dependent transcriptional activation, and GATA3 binds to this site. In addition, forced expression of GATA3 potentiated the induction ofRALDH2 by TAL1 and LMO, and these three factors formed a complex in vivo. Furthermore, a TAL1 mutant not binding to DNA also activated the transcription of RALDH2 in the presence of LMO and GATA3. Collectively, we have identified the RALDH2 gene as a first example of direct transcriptional target genes regulated by TAL1 and LMO in T-ALL. In this case, TAL1 and LMO act as cofactors for GATA3 to activate the transcription ofRALDH2.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

scholarly journals miR-101 Represses T-Cell Acute Lymphoblastic Leukemia by Targeting CXCR7/STAT3 Axis

2019 ◽  
Vol 27 (9) ◽  
pp. 997-1006 ◽  
Author(s):  
Xue-Yi Yang ◽  
Ye Sheng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Inhibitory Effects ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Direct Target ◽  
Proliferation And Invasion

Although miR-101 is involved in the development and progression of T-cell acute lymphoblastic leukemia (T-ALL), the underlying molecular mechanisms remain unclear. In this article, we report that miR-101 expression was inversely correlated with CX chemokine receptor 7 (CXCR7) level in T-ALL. Introducing miR-101 inhibited T-ALL cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis in vivo. CXCR7 was identified as a direct target of miR-101. The inhibitory effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. Mechanistically, miR-101 targets CXCR7/STAT3 axis to reduce T-ALL growth and metastasis. Overall, these findings implied the potential application of miR-101 and CXCR7 in T-ALL treatment.

scholarly journals Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kehan Li ◽  
Cunte Chen ◽  
Rili Gao ◽  
Xibao Yu ◽  
Youxue Huang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Growth Retardation ◽  
Lymphoblastic Leukemia ◽  
Downstream Target ◽  
B Cell Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Aggressive Subtype

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

scholarly journals Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2291-2304 ◽  
Author(s):  
Diego Sánchez-Martínez ◽  
Matteo L. Baroni ◽  
Francisco Gutierrez-Agüera ◽  
Heleia Roca-Ho ◽  
Oscar Blanch-Lombarte ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Antileukemic Activity ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.

Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia

2017 ◽  
Vol 405 ◽  
pp. 73-78 ◽  
Author(s):  
Sausan A. Moharram ◽  
Kinjal Shah ◽  
Fatima Khanum ◽  
Alissa Marhäll ◽  
Mohiuddin Gazi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cdk Inhibitor ◽  
Cell Acute Lymphoblastic Leukemia

Deletion of Atm in the Hematopoetic Stem Cell As a Mouse Model for Human T Cell Acute Lymphoblastic Leukemia/Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2418-2418
Author(s):  
Lori A. Ehrlich ◽  
Katherine S. Yang-Iott ◽  
Amy DeMicco ◽  
Craig H. Bassing
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Drug Combinations ◽  
Thymic Epithelial Cells ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 2418 Acute lymphoblastic leukemia (ALL) is diagnosed in approximately 2500 children per year. Although high cure rates have been achieved for ALL, these cancers account for the highest number of non-brain tumor cancer-related deaths in children. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature TCRβ−CD4+/CD8+ T-cells that represents ∼15% of pediatric ALL diagnoses, comprises most of the therapy-resistant ALL tumors, and exhibits a high frequency of relapse. The Ataxia Telangiectasia mutated (ATM) protein kinase activates the cellular response to DNA double strand breaks (DSBs) to coordinate DNA repair with cell survival, proliferation, and differentiation. Somatic inactivating ATM mutations occur in 10–20% of T-ALL and T cell lymphoblastic lymphoma (T-LL) tumors and are associated with resistance to genotoxic chemotherapy drugs and therapy relapse, likely driven by increased genomic instability in cells lacking functional ATM. The impaired DSB response of ATM-deficient cells can be exploited to design combinations of genotoxic drugs that specifically kill these cells in vitro. However, the in vivo potential of such drug combinations to treat T-ALL have not been reported. We sought to develop a pre-clinical mouse model that could be used to test effectiveness of such drug combinations to treat T-ALLs and T-LLs with somatic ATM inactivation. Although germline ATM-deficient (Atm−/−) mice succumb by six months of age to immature CD4+/CD8+ T-cell lymphomas containing genomic instability analogous to human T-ALL tumors, we sought a more physiologic model that would avoid potential complications due to ATM-deficiency in thymic epithelial cells. Thus, we generated and characterized VavCre:Atmflox/flox mice with conditional Atm inactivation restricted to hematopoietic cell lineages. These mice contain reduced numbers of TCRβ−CD4+/CD8+, TCRβ+CD4+/CD8−, and TCRβ+CD4−/CD8+ thymocytes and of TCRβ+CD4+ and TCRb+CD8+ splenic T-cells, mirroring the phenotype of Atm−/− mice. We have found that VavCre:Atmflox/flox mice succumb at an average of 95 days (range 53–183 days) to clonal TCRβ−CD4+/CD8+ or TCRβ+CD4−/CD8+ thymic lymphomas. Evaluation of the bone marrow in a subset of these mice indicates that the lymphoma has disseminated and are classified as leukemia. Our initial cytogenetic analyses of these tumors indicate that they contain both clonal translocations involving chromosome 12 and/or chromosome 14 and deletion of one allelic copy of the haploinsufficient Bcl11b tumor suppressor gene. Hemizygous BCL11B inactivation occurs in ∼20% of human T-ALL tumors, indicating the clinical relevance of VavCre:Atmflox/flox mice as a model for human T-ALL. Our ongoing studies include complete cytogenetic and molecular characterization of VavCre:Atmflox/flox tumors and in vivo testing of chemotherapeutics targeting the Atm pathway in this mouse model of T-ALL/T-LL. Disclosures: No relevant conflicts of interest to declare.

Epigenetic Control Of Cell Cycle-Promoting Genes By Ikaros and Casein Kinase II In B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3734-3734
Author(s):  
Sinisa Dovat ◽  
Chunhua Song ◽  
Xiaokang Pan ◽  
Yali Ding ◽  
Chandrika S. Gowda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Regulatory Elements ◽  
Preclinical Model ◽  
Cycle Arrest ◽  
Cell Acute Lymphoblastic Leukemia

Abstract IKZF1 (Ikaros) encodes a kruppel-like zinc finger protein that is essential for normal hematopoiesis and acts as a tumor suppressor in acute lymphoblastic leukemia (ALL). The deletion and/or mutation of Ikaros is associated with the development of human T-cell and B-cell acute lymphoblastic leukemia (B-ALL) with poor outcome. In vivo, Ikaros binds DNA and regulates gene expression by chromatin remodeling. Since there is a paucity of known genes that are regulated by Ikaros, the molecular mechanisms through which Ikaros exerts its tumor suppressor function remain unknown. Here we describe studies that identify the targets and mechanisms of Ikaros-mediated epigenetic regulation in human B-ALL. We used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-seq) to identify target genes that are bound by Ikaros in vivo in human B-ALL, and to define epigenetic patterns associated with Ikaros binding. ChIP-seq revealed a large set of Ikaros target genes that contain a characteristic Ikaros binding motif. The largest group of genes that are direct Ikaros targets included genes that are essential for cell cycle progression. These included CDC2, CDC7, CDK2 and CDK6 genes whose deregulation is associated with malignant transformation. The strong binding of ikaros to the promoters of cell cycle-promoting genes was confirmed by quantitative immunoprecipitation in primary leukemia cells. To establish whether Ikaros directly regulates transcription of the cell cycle-promoting genes, their expression was measured in B-ALL cells that were transduced with either a retroviral vector that contains Ikaros, or a control vector. Target gene expression was monitored by qRT-PCR. Ikaros strongly repressed transcription of the cell cycle-promoting genes, which resulted in cell cycle arrest. Global epigenetic profiling using ChIP-seq suggested that Ikaros represses cell cycle-promoting genes by inducing epigenetic changes that are consistent with repressive chromatin. High-resolution epigenetic profiling of the upstream regulatory elements of the cell cycle-promoting genes targeted by Ikaros showed that increased Ikaros expression results in the formation of heterochromatin, which is characterized by the presence of the H3K9me3 histone modification and associated transcriptional repression. Functional analysis revealed that phosphorylation of Ikaros by the oncogenic protein. Casein kinase II (CK2), impairs its function as a transcriptional repressor of the cell cycle-regulating genes. Inhibition of CK2 by specific inhibitors enhances Ikaros-mediated repression of the cell cycle-regulating genes resulting in cessation of cellular proliferation and cell cycle arrest in vitro and in vivo in a B-cell ALL preclinical model. This was associated with increased Ikaros binding and the formation of heterochromatin at upstream regulatory elements of the cell cycle-promoting genes. Our results provide evidence that Ikaros functions as a repressor of cell cycle-promoting genes in B-ALL by directly binding their promoters and inducing the formation of heterochromatin with characteristic H3K9me3 histone modifications Ikaros repressor function is negatively regulated by CK2 kinase in B-cell ALL. Inhibition of CK2 enhances Ikaros mediated-repression of cell cycle-promoting genes resulting in an anti-leukemia effect in a preclinical model of B-cell ALL. Presented data identified the mechanism of action of CK2 inhibitors and demonstrated their efficacy in B-cell ALL preclinical model. Results support the use of CK2 inhibitors in Phase I clinical trial. Supported by National Institutes of Health R01 HL095120 and a St. Baldrick’s Foundation Career Development Award (to S.D.). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of JAK1/2 and BCL2 inhibition on human T cell acute lymphoblastic leukemia in vitro and in vivo

2019 ◽  
Author(s):  
Kirsti L. Walker ◽  
Sabrina A. Kabakov ◽  
Fen Zhu ◽  
Myriam N. Bouchlaka ◽  
Sydney L Olson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Combination Treatment ◽  
Lymphoblastic Leukemia ◽  
Jurkat Cells ◽  
Human T Cell ◽  
Liquid Chromatography Tandem Mass ◽  
Cell Acute Lymphoblastic Leukemia

AbstractRelapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) is difficult to salvage especially in heavily pretreated patients, thus novel targeted agents are sorely needed. Hyperactivated JAK/STAT and BCL2 overexpression promote increased T-ALL proliferation and survival, and targeting these pathways with ruxolitinib and venetoclax may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect individually, but combination treatment synergistically reduces survival and proliferation of Jurkat and Loucy cells in vitro. Using a xenograft CXCR4+ Jurkat model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS), which expresses CXCL12, as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that neither ruxolitinib nor venetoclax can effectively cross the blood-brain barrier, limiting efficacy against CNS T-ALL. Deletion of CXCR4 on Jurkat cells by CRISPR/Cas9 results in prolonged survival and a reduction in overall and neurologic clinical scores. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis will be needed to eliminate both systemic and CNS T-ALL burden and maximize the possibility of complete remission.

Inv(11)(q21q23) Fuses MLL to the NOTCH Co-Activator Mastermind-Like 2 in Secondary T Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4284-4284
Author(s):  
Markus Metzler ◽  
Jan Zuna ◽  
Martin S. Staege ◽  
Lana Harder ◽  
Claus Meyer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transcriptional Activation ◽  
Selection Process ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Fusion Partner ◽  
Secondary Leukemia ◽  
Transcriptional Activation Domain ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Development of a secondary leukemia after chemotherapeutic treatment for childhood acute leukemia is associated with rearrangements of the MLL gene on chromosome 11q23 and characteristically results in acute myeloid leukemia (AML). We identified the NOTCH co-activator Mastermind-like 2 as MLL fusion partner in two cases of pediatric secondary leukemia. The MLL-MAML2 fusion results from a cryptic inv(11)(q21q23) only detectable by interphase fluorescence in situ hybridization with an MLL split signal probe. With a latency of twenty months and five years after initial diagnosis for MLL negative AML and precursor B acute lymphoblastic leukemia (ALL), respectively, both patients developed a therapy-related T-cell acute lymphoblastic leukemia. MAML2 is the first MLL fusion partner involved in human Notch-signaling and was only recently identified as recurrent translocation fusion partner in a subset of salivary gland tumors. The genomic MLL breakpoint shows similar localization and sequence features described for etoposide induced treatment-related AML. MLL-MAML2 positive cells were detectable up to two years prior to clinical apparent secondary leukemia in one case. The discrepant dynamics of clone expansion quantified by either the genomic fusion sequence or Ig/TCR gene rearrangements as clone specific markers suggests a selection process within the inversion positive population and the need for additional mutation events to promote overt leukemic disease. Whole genome expression profiles demonstrated differential expression of both typical MLL and NOTCH downstream genes, which suggests a modulatory role of the MAML2 transcriptional activation domain in MLL leukemogenesis and lineage assignment induced by the MLL-MAML2 fusion protein. MSM21620813 WSF3401600.

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