Gene Summary

Gene:TCL1A; T cell leukemia/lymphoma 1A
Aliases: TCL1
Summary:Overexpression of the TCL1 gene in humans has been implicated in the development of mature T cell leukemia, in which chromosomal rearrangements bring the TCL1 gene in close proximity to the T-cell antigen receptor (TCR)-alpha (MIM 186880) or TCR-beta (MIM 186930) regulatory elements (summarized by Virgilio et al., 1998 [PubMed 9520462]). In normal T cells TCL1 is expressed in CD4-/CD8- cells, but not in cells at later stages of differentiation. TCL1 functions as a coactivator of the cell survival kinase AKT (MIM 164730) (Laine et al., 2000 [PubMed 10983986]).[supplied by OMIM, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-cell leukemia/lymphoma protein 1A
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunohistochemistry
  • Proto-Oncogene Proteins
  • Leukemia, Prolymphocytic
  • Transfection
  • Up-Regulation
  • T-Cell Leukemia
  • Molecular Sequence Data
  • Adolescents
  • Gene Expression
  • Base Sequence
  • Mutation
  • Leukaemia
  • B-Cell Lymphoma
  • Cell Differentiation
  • MicroRNAs
  • Childhood Cancer
  • T-Lymphocytes
  • DNA-Binding Proteins
  • Oncogenes
  • TCL1A
  • Leukemia, Prolymphocytic, T-Cell
  • Mice, Transgenic
  • Chronic Lymphocytic Leukemia
  • Disease Models, Animal
  • Gene Expression Profiling
  • B-Lymphocytes
  • Leukemic Gene Expression Regulation
  • Transcription Factors
  • Flow Cytometry
  • Disease Progression
  • Messenger RNA
  • Amino Acid Sequence
  • Chromosome Aberrations
  • Chromosome 14
  • Translocation
  • Neoplasm Proteins
  • Cancer Gene Expression Regulation
  • FISH
  • Biomarkers, Tumor
  • Diffuse Large B-Cell Lymphoma
  • Phenotype
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TCL1A (cancer-related)

Tari K, Shamsi Z, Reza Ghafari H, et al.
The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.
Exp Oncol. 2018; 40(4):261-267 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

Khoury JD
Blastic Plasmacytoid Dendritic Cell Neoplasm.
Curr Hematol Malig Rep. 2018; 13(6):477-483 [PubMed] Related Publications
PURPOSE OF REVIEW: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy derived from plasmacyoid dendritic cells whose biology, clinical features, and treatment options are increasingly better understood.
RECENT FINDINGS: TCF4 is a master regulator that drives donwstream transcriptional programs in BPDCN. In turn, TCF4 activity is dependent on the bromodomain and extra-terminal domain (BET) protein BRD4 whose inhibition provides a promising therapeutic vulnerability. Notably, TCF4 expression is a highly sensitive marker for BPDCN and augments diagnostic specificity alongside CD4, CD56, CD123, and TCL1. The gene expression profile of BPDCN is characterized by aberrant NF-kappaB pathway activation, while its genomic landscape is dominated by structural chromosomal alterations involving ETV6, MYC, and NR3C1, as well as mutations in epigenetic regulators particularly TET2. Advances in elucidating the biological characteristics of BPDCN are resulting in a more refined diagnostic approach and are opening novel therapeutic avenues for patients with this disease.

McMaster ML, Berndt SI, Zhang J, et al.
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.
Nat Commun. 2018; 9(1):4182 [PubMed] Free Access to Full Article Related Publications
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10

Sumarriva Lezama L, Chisholm KM, Carneal E, et al.
An analysis of blastic plasmacytoid dendritic cell neoplasm with translocations involving the MYC locus identifies t(6;8)(p21;q24) as a recurrent cytogenetic abnormality.
Histopathology. 2018; 73(5):767-776 [PubMed] Related Publications
AIMS: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm with leukaemic features and frequent skin involvement. Translocations involving the MYC locus have been recently identified as recurrent cytogenetic abnormalities in this entity. The aim of this study was to assess the clinicopathological, immunophenotypic and genetic features in MYC-rearranged BPDCN cases.
METHODS AND RESULTS: Pathology archives from six major institutes were queried for cases of BPDCN with 8q24 MYC translocations, and two cases were identified. A literature review identified 14 cases. Clinicopathological features, immunophenotype and cytogenetic and molecular data were reviewed. In these 16 MYC-rearranged cases, the median age at diagnosis was 70.5 years, and there was a male predominance. Whereas all cases showed marrow involvement, skin lesions (62.5%) and lymphadenopathy (50%) were variably seen. The median survival was 11 months. The median percentage of blasts in peripheral blood was 9%. All cases showed expression of CD4, with 10 of 16 being positive for CD56. HLA-DR, CD123, TCL1 and CD303 were positive in all cases tested. Cytogenetic analysis revealed a single recurrent translocation partner of MYC at 6p21 in 11 cases (69%), whereas four cases showed different MYC translocation partners (2p12, Xq24, 3p25, and 14q32). Interestingly, the group of patients with t(6;8)(p21;q24) showed an older median age at diagnosis (74 years) and a remarkably shorter median survival (3 months).
CONCLUSIONS: Translocations involving the 8q24 MYC locus more frequently manifest as t(6;8)(p21;q24), and, given its association with specific clinicopathological features suggesting even more aggressive behaviour, t(6;8)(p21;q24) indicate a genetically defined subgroup within BPDCN.

Leung CS
Analysis of ROR1 Protein Expression in Mice with Reconstituted Human Immune System Components.
J Immunol Res. 2018; 2018:2480931 [PubMed] Free Access to Full Article Related Publications
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal antigen expressed on multiple tumors and has no significant expression on normal human tissues. ROR1 is highly upregulated in chronic lymphocytic leukemia (CLL) B cells. NOD-scid IL2rg

McKenna MK, Noothi SK, Alhakeem SS, et al.
Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia.
Blood. 2018; 131(26):2943-2954 [PubMed] Free Access to Full Article Related Publications
Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)-approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors.

Dai J, Ma J, Yu B, et al.
Long Noncoding RNA TUNAR Represses Growth, Migration, and Invasion of Human Glioma Cells Through Regulating miR-200a and Rac1.
Oncol Res. 2018; 27(1):107-115 [PubMed] Related Publications
Glioma is the most common primary adult brain tumor. Mounting research has illustrated the function of long noncoding RNAs (lncRNAs) in glioma progress, but almost no studies have reported the role of TCL1 upstream neural differentiation-associated RNA (TUNAR) in glioma cells. This study aimed to investigate the function of TUNAR in glioma. The GL15 cell line was used in this study. The interactions between TUNAR and miR-200a, or miR-200a and Rac1 were determined by cotransfection experiments. TUNAR overexpression significantly inhibited glioma malignancy by decreasing cell viability, migration, and invasion and promoting cell apoptosis. TUNAR was confirmed to positively regulate miR-200a, and knockdown of miR-200a reversed the TUNAR-induced inhibitory effects on glioma cells. Further, Rac1 was negatively regulated by miR-200a. Rac1 overexpression abolished miR-200a overexpression-induced inhibition of viability, migration, and invasion, as well as the increase in apoptosis. Rac1 knockdown inhibited glioma by inactivating the Wnt/β-catenin and NF-κB signaling pathways. Our findings suggested that TUNAR played an anticancer role in glioma cells by upregulating miR-200a and inhibiting Rac1, and so might represent a potential therapeutic target for the treatment of human glioma.

Schrader A, Crispatzu G, Oberbeck S, et al.
Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.
Nat Commun. 2018; 9(1):697 [PubMed] Free Access to Full Article Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Mazzoccoli L, Robaina MC, Apa AG, et al.
MiR-29 silencing modulates the expression of target genes related to proliferation, apoptosis and methylation in Burkitt lymphoma cells.
J Cancer Res Clin Oncol. 2018; 144(3):483-497 [PubMed] Related Publications
PURPOSE: Burkitt lymphoma (BL) is a B-cell lymphoma frequently diagnosed in children. It is characterized by MYC translocations, which lead to the constitutive expression of the MYC oncogene. MYC contributes to miR-29 repression through an E-box MYC binding site on the miR-29b-1/miR-29a promoter region. We evaluated the role of miR-29a/b/c and their predicted targets in BL pathogenesis.
METHODS: Mature sequences of miR-29a/b/c were transfected to the BL cell lines BL41 and Raji, and evaluated for DNMT3B, MCL1, BIM, CDK6, AKT and TCL1 protein expression as well as for MCL-1 and CDK6 mRNA expression. BL cells were treated with 5-aza-2'-deoxycytidine (decitabine) and evaluated for miR29 expressions and methylation status. DNMT3B inhibition was performed by DNMT3B siRNA.
RESULTS: Ectopic expression of miR-29s in BL cells decreased CDK6, DNMT3B, TCL1 and MCL-1 protein levels, but CDK6 and MCL-1 mRNA expression was unaffected by miR-29. Decitabine enhanced miR-29 expression levels and decreased CDK6 protein expression. Additionally, inhibition of DNMT3B by siRNA increased miR-29a/b expression. Notably, the miR-29a/b1 and miR-29b2/c promoter genes showed methylated CpG sequences that were demethylated after decitabine treatments. Furthermore, MYC-negative tumours had higher levels of miR-29 expression compared with MYC-translocated cases, suggesting that MYC regulates miR-29 in BL tumours.
CONCLUSIONS: Our results suggest a significant role for miR-29s in BL pathogenesis in altering the expression of targets involved in critical cancer pathways, such as cell cycle control, apoptosis inhibition and DNA methylation. Moreover, methylation-mediated miR-29 epigenetic silencing may occur during BL development.

Janovska P, Verner J, Kohoutek J, et al.
Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia.
Blood. 2018; 131(11):1206-1218 [PubMed] Related Publications
Casein kinase 1δ/ε (CK1δ/ε) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

Balatti V, Pekarsky Y, Croce CM
Role of the tRNA-Derived Small RNAs in Cancer: New Potential Biomarkers and Target for Therapy.
Adv Cancer Res. 2017; 135:173-187 [PubMed] Related Publications
Noncoding RNAs are untranslated RNA molecules that can be divided into two main types: infrastructural, including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and regulatory, including long ncRNAs (lncRNAs) and small ncRNAs (sRNA). Among small ncRNA, the role of microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in cancer is well documented. Recently, other small ncRNAs have been described. In particular, tRNA-derived small RNAs (tsRNA) have been found to be frequently dysregulated in cancer. Since tsRNAs can be considered unique sequences and are able to bind both Argonaute proteins (like miRNAs) and Piwi proteins (like piRNAs), their dysregulation could play a critical role in cancer by interfering with gene expression regulation at different levels. Like microRNAs, ts-53 (previously known as miR-3676) interacts with the 3'UTR of TCL1, therefore supporting a role for tsRNAs on the posttranscriptional regulation of gene expression. Like piRNAs, tsRNAs are produced as single-stranded molecules and can interact with DNA and histone methylation machinery, suggesting a role in the pretranscriptional regulation of gene expression. Herein, we describe the most recent findings about the role of tsRNAs in cancer.

D'Abundo L, Callegari E, Bresin A, et al.
Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model.
Oncogene. 2017; 36(47):6617-6626 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eμ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody. This methodology has proven to be highly effective in delivering miRNA molecules into leukemic cells. Short- and long-term experiments showed that miR-26a, miR-130a and anti-miR-155 increased apoptosis after in vitro and in vivo treatment. Of this miRNA panel, miR-26a was the most effective in reducing leukemic cell expansion. Following long-term treatment, apoptosis was readily detectable by analyzing cleavage of PARP and caspase-7. These effects could be directly attributed to miR-26a, as confirmed by significant downregulation of its proven targets, namely cyclin-dependent kinase 6 and Mcl1. The results of this study are relevant to two distinct areas. The first is related to the design of a technical strategy and to the selection of CD38 as a molecular target on CLL cells, both consenting efficient and specific intracellular transfer of miRNA. The original scientific finding inferred from the above approach is that miR-26a can elicit in vivo anti-leukemic activities mediated by increased apoptosis.

Niemann CU, Mora-Jensen HI, Dadashian EL, et al.
Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model.
Clin Cancer Res. 2017; 23(19):5814-5823 [PubMed] Free Access to Full Article Related Publications

Burns A, Alsolami R, Becq J, et al.
Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHV
Leukemia. 2018; 32(2):332-342 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHV

Hu Z, Li S, Medeiros LJ, Sun T
TCL-1-positive hematogones in a patient with T-cell prolymphocytic leukemia after therapy.
Hum Pathol. 2017; 65:175-179 [PubMed] Related Publications
T-prolymphocytic leukemia (T-PLL) is a rare mature T-cell neoplasm characterized by proliferation of prolymphocytes. Most cases involve the T-cell leukemia-1 (TCL1) gene at 14q11.2 resulting in overexpression of TCL-1, which is helpful for distinguishing T-PLL from other T-cell neoplasms. We report a patient with T-PLL whose leukemic cells were positive for TCL-1 by immunohistochemistry but with a normal karyotype. The patient had anti-CD52 antibody therapy for 12 weeks. In a follow-up bone marrow biopsy specimen, numerous TCL-1-positive cells were present, which raised the differential diagnosis of residual T-PLL. However, further immunophenotypic studies confirmed that these cells were hematogones. Therefore a diagnosis of recovering bone marrow was established. The patient underwent stem cell transplant and is now in complete remission. This case demonstrates that hematogones can express TCL-1, and this knowledge is very important for the differential diagnosis in the follow-up marrow of T-PLL patients.

Li H, Yan X, Liu L, et al.
T-cell leukemia/lymphoma-1A predicts the clinical outcome for patients with stage II/III colorectal cancer.
Biomed Pharmacother. 2017; 88:924-930 [PubMed] Related Publications
T-cell leukemia/lymphoma-1A (TCL1A) as a stem cell marker is abundantly expressed in embryonic stem cells and has been identified as an oncogene in various hematological malignancies such as chronic lymphocytic leukemia and B-cell lymphoma. However, with regard to its role in solid tumors, few studies are available and less are for colorectal cancer (CRC). In this study, we aim to investigate the expression and clinical significance of TCL1A in a cohort of 278 stage II/III CRC patients. As a result, we find TCL1A expression is higher in CRC tissues than that in adjacent normal tissues, and significantly correlated with tumor differentiation, TNM stage and Ki-67 positive rate. The prognostic analysis suggests that TCL1A expression is an independent factor affecting CRC-specific and disease-free survival of these patients. Furthermore, we find stage II/III patients with high TCL1A expression have a significantly higher rate of postoperative local recurrence and metastasis than those with low TCL1A expression. Finally, through subgroup analysis, we find TCL1A expression can stratify the outcome of stage II/III patients who received standard adjuvant chemotherapy. Taken together, our findings suggest TCL1A is not only a useful biomarker for prognostic evaluation in stage II/III CRC patients, but also a promising therapeutic target for improving their clinical outcome.

Shao Y, Zhang Y, Hou Y, et al.
A novel long noncoding RNA PILRLS promote proliferation through TCL1A by activing MDM2 in Retroperitoneal liposarcoma.
Oncotarget. 2017; 8(8):13971-13978 [PubMed] Free Access to Full Article Related Publications
It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in retroperitoneal liposarcoma have never been reported. In our study, we found a novel lncRNA PILRLS (Proliferation Interacting LncRNA in Retroperitoneal Liposarcoma), which as an oncogene significantly overexpressed in retroperitoneal liposarcoma. Functions of PILRLS on tumor progression both in vitro and in vivo have verified in this study which PILRLS knockdown significantly inhibited cell proliferation and colony formation. RNA pull-down assay found PILRLS can specific binding with TCL1A which also regulate the expression level of TCL1A. Our work for the first time demonstrated PILRLS can activating the MDM2 by binding with TCL1A which suppress the P53 pathway to promote the unlimited growth of retroperitoneal Liposarcoma cells. It suggests that PILRLS may be an important targets for retroperitoneal liposarcoma therapy.

Mirzaei H, Fathullahzadeh S, Khanmohammadi R, et al.
State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia.
J Cell Physiol. 2018; 233(2):888-900 [PubMed] Related Publications
Early diagnostic is one of the most important steps in cancer therapy which helps to design and choose a better therapeutic approach. The finding of biomarkers in various levels including genomics, transcriptomics, and proteomics levels could provide better treatment for various cancers such as chronic lymphocytic leukemia (CLL). The CLL is the one of main lymphoid malignancies which is specified by aggregation of mature B lymphocytes. Among different biomarkers (e.g., CD38, chromosomes abnormalities, ZAP-70, TP53, and microRNA [miRNA]), miRNAs have appeared as new diagnostic and therapeutic biomarkers in patients with the CLL disease. Multiple lines of evidence indicated that deregulation of miRNAs could be associated with pathological events which are present in the CLL. These molecules have an effect on a variety of targets such as Bcl2, c-fos, c-Myc, TP53, TCL1, and STAT3 which play critical roles in the CLL pathogenesis. It has been shown that expression of miRNAs could lead to the activation of B cells and B cell antigen receptor (BCR). Moreover, exosomes containing miRNAs are one of the other molecules which could contribute to BCR stimulation and progression of CLL cells. Hence, miRNAs and exosomes released from CLL cells could be used as potential diagnostic and therapeutic biomarkers for CLL. This critical review focuses on a very important aspect of CLL based on biomarker discovery covers the pros and cons of using miRNAs as important diagnostics and therapeutics biomarkers for this deadly disease.

Johnston HE, Carter MJ, Cox KL, et al.
Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures.
Mol Cell Proteomics. 2017; 16(3):386-406 [PubMed] Free Access to Full Article Related Publications
Approximately 800,000 leukemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukemia (CLL) are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumor, frequently affecting children, whereas CLL typically presents as an indolent, slow-progressing leukemia affecting the elderly. The B-cell-specific overexpression of the

Cui B, Ghia EM, Chen L, et al.
High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia.
Blood. 2016; 128(25):2931-2940 [PubMed] Free Access to Full Article Related Publications
ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1

Gervasini G, Jara C, Olier C, et al.
Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients.
Br J Clin Pharmacol. 2017; 83(3):562-571 [PubMed] Free Access to Full Article Related Publications
AIMS: Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series.
METHODS: This study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models.
RESULTS: Anastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95 ± 11.91 ng ml
CONCLUSION: Our findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.

Lee HJ, Gallardo M, Ma H, et al.
p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL.
Blood Cancer J. 2016; 6:e434 [PubMed] Free Access to Full Article Related Publications
Deletion of the short-arm of chromosome 17 (17p-) is one of the most critical genetic alterations used in chronic lymphocytic leukemia (CLL) risk stratification. The tumor suppressor TP53 maps to this region, and its loss or mutation accelerates CLL progression, hampers response to chemotherapy and shortens survival. Although florescent in situ hybridization analyses for 17p deletions are routinely performed during clinical diagnoses, p53 mutational status is often unexamined. Given the limited clinical data that exists for frontline treatment of patients with CLL harboring TP53 mutations, there is a need to understand the biology of CLL with TP53 mutations and identify treatment strategies for this subset of patients. Herein, we used a CLL mouse model (Eμ-TCL1) harboring one of the most common TP53 hot-spot mutations observed in CLL (p53(R172H), corresponding to p53(R175H) in humans) to evaluate its impact on disease progression, survival, response to therapy and loss of the remaining wild-type Trp53 allele following ibrutinib treatment. We show that ibrutinib was effective in increasing survival, activating cellular programs outside the p53 pathway and did not place selective pressure on the remaining wild-type Trp53 allele. These data provide evidence that ibrutinib acts as an effective treatment for aggressive forms of CLL with TP53 mutations.

Pekarsky Y, Balatti V, Palamarchuk A, et al.
Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer.
Proc Natl Acad Sci U S A. 2016; 113(18):5071-6 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis. We found that, like ts-3676, ts-4521 is down-regulated and mutated in CLL. Analysis of lung cancer samples revealed that both ts-3676 and ts-4521 are down-regulated and mutated in patient tumor samples. Because tsRNAs are similar in nature to piRNAs [P-element-induced wimpy testis (Piwi)-interacting small RNAs], we investigated whether ts-3676 and ts-4521 can interact with Piwi proteins and found these two tsRNAs in complexes containing Piwi-like protein 2 (PIWIL2). To determine whether other tsRNAs are involved in cancer, we generated a custom microarray chip containing 120 tsRNAs 16 bp or more in size. Microarray hybridization experiments revealed tsRNA signatures in CLL and lung cancer, indicating that, like microRNAs, tsRNAs may have an oncogenic and/or tumor-suppressor function in hematopoietic malignancies and solid tumors. Thus, our results show that tsRNAs are dysregulated in human cancer.

López C, Bergmann AK, Paul U, et al.
Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia.
Br J Haematol. 2016; 173(2):265-73 [PubMed] Related Publications
T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.

Bresin A, D'Abundo L, Narducci MG, et al.
TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia.
Cell Death Dis. 2016; 7:e2071 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets.

Hunter JE, Butterworth JA, Zhao B, et al.
The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.
Oncogene. 2016; 35(26):3476-84 [PubMed] Free Access to Full Article Related Publications
The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel-/- mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel-/- Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel-/- Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel-/- TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel-/- mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in cancer.

Hanna BS, McClanahan F, Yazdanparast H, et al.
Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.
Leukemia. 2016; 30(3):570-9 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eμ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.

Lemal R, Bard-Sorel S, Montrieul L, et al.
TCL1 expression patterns in Waldenström macroglobulinemia.
Mod Pathol. 2016; 29(1):83-8 [PubMed] Related Publications
The oncogenic role of TCL1 in chronic lymphocytic leukemia is well established in transgenic mice. TCL1 expression in other B-cell malignancies has been also described: post-germinal center-derived malignancies, such as multiple myeloma, classically do not express TCL1. Waldenström macroglobulinemia is a post-germinal center malignancy that is known to be similar to chronic lymphocytic leukemia in terms of its gene expression profile. TCL1 expression has not been so far assessed in Waldenström macroglobulinemia. Transcriptomic explorations show that TCL1A expression is linked to signaling pathways and biological functions that are known to be involved in Waldenström macroglobulinemia as well as to gene signatures of interest in B-cell malignancies. We investigated TCL1 expression at the protein level in the bone marrow of a series of 59 patients with Waldenström macroglobulinemia: 76% of patients expressed TCL1, which appeared to be associated with a pejorative prognostic impact. TCL1 could have an oncogenic role in Waldenström macroglobulinemia, and deserves further exploration.

Stengel A, Kern W, Zenger M, et al.
Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker.
Genes Chromosomes Cancer. 2016; 55(1):82-94 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T-PLL comprising the largest cohort of patients with T-PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T-PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T-PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto-oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact.

Martinez D, Navarro A, Martinez-Trillos A, et al.
NOTCH1, TP53, and MAP2K1 Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease.
Am J Surg Pathol. 2016; 40(2):192-201 [PubMed] Related Publications
Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.

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