Alternative titles; symbols
HGNC Approved Gene Symbol: TAL1
Cytogenetic location: 1p33 Genomic coordinates (GRCh38) : 1:47,216,290-47,232,335 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p33 | Leukemia, T-cell acute lymphocytic, somatic | 613065 | 3 |
TAL1 is a transcriptionally complex gene that is expressed throughout development, activating or repressing transcription in hematopoietic, neural, and endothelial precursors (summary by Hosur et al., 2013).
Finger et al. (1989) analyzed a t(1;14)(p32;q11) chromosomal translocation in a lymphohemopoietic stem cell line derived from a patient with acute T-lymphoblastic leukemia (Kurtzberg et al., 1985). They found that the segment of chromosome 1p32 adjacent to the chromosomal breakpoint encodes a transcriptional unit that they designated TCL5.
Begley et al. (1989) studied a leukemic stem cell line capable of differentiating into either myeloid or lymphoid cells that carried a t(1;14)(p33;q11) translocation. The chromosome 1 region involved in the breakpoint was the site of transcriptional activity apparently occurring only in hematopoietic tissues. Begley et al. (1989) concluded that the translocation may identify a gene on chromosome 1 that is important for hematopoietic development and oncogenesis, and they suggested the gene designation SCL. Chen et al. (1990) concluded that the TAL1 gene encodes a helix-loop-helix protein with homology to LYL1 (151440), which is also involved in malignant development of lymphocytes.
Begley et al. (1991) isolated a murine Scl cDNA and found that the encoded protein shares 94% amino acid identity with human SCL. The helix-loop-helix motif and upstream hydrophilic regions are entirely conserved in the murine and human proteins. In the murine Scl cDNA, a long ORF begins with the sequence CCCAGGATGA, which is in agreement with the Kozak consensus sequence for translational initiation (Kozak, 1987).
Hosur et al. (2013) found expression of the Tal1 gene in mouse kidney. Strongest expression was observed in the embryo between days 13 and 17; expression rapidly decreased after birth, but remained low in adult kidney.
In a review, Xia et al. (1991) stated that the TAL1 gene product is homologous to proteins involved in control of cell growth and differentiation. The region of homology is restricted to a 56-amino acid domain that forms 2 amphipathic helices separated by an intervening loop. Such helix-loop-helix (HLH) proteins are thought to function as transcriptional regulatory factors based on their ability to bind in vitro to the E-box motif (CANNTG) of eukaryotic transcriptional enhancers. Enhancer-binding HLH proteins include E47 and E12, 2 distinct but related polypeptides encoded by the E2A gene (147141). The E2A gene products can form heterologous complexes, presumably heterodimers, with other HLH proteins, and these heterodimers also bind the E-box sequence with high affinity. Since TAL1 polypeptides form heterologous complexes in vitro with either E47 or E12, and since the resultant heterodimers specifically recognize the E-box motif, the TAL1 gene product may also function in vivo as a transcriptional regulatory factor. The HLH domains of TAL1 and LYL1 (151440), a gene that was also identified on the basis of tumor-specific rearrangement in human T-cell leukemia, share 87% amino acid sequence identity. TAL2 (186855) is another HLH gene implicated in human T-cell acute lymphoblastic leukemia (T-ALL).
Muroyama et al. (2005) showed that mouse Tal1 had multiple functions in regulation of both astrocyte versus oligodendrocyte cell fate acquisition and V2b versus V2a interneuron cell fate acquisition in the p2 domain of developing vertebrate spinal cord. Their findings demonstrated a regionally restricted transcriptional program necessary for astrocyte and V2b interneuron development, with striking parallels to the involvement of TAL1 in hematopoiesis. Their findings also suggested that acquisition of embryonic glial subtype identity might be regulated by genetic interactions between TAL1 and the transcription factor OLIG2 (606386) in the ventral neural tube.
Goardon et al. (2006) found that ETO2 (CBFA2T3; 603870) copurified with TAL1 complexes in human and mouse erythroleukemia cells. Protein pull-down assays revealed that ETO2 interacted with E2A and HEB (TCF12; 600480) within the TAL1 complex, but not with TAL1 itself. ETO2 also interacted with E2A in erythroid cells independent of the TAL1 complex. Reporter gene assays revealed that ETO2 repressed the transcriptional activity of the complex. The ETO2 content in TAL1 complexes was high during the proliferative phase in erythroid cells. In contrast, ETO2 was downregulated upon terminal differentiation, concomitant with appearance of histone modifications associated with gene activation and expression of glycophorin A (GPA; 617922) and band 4.2 (EPB42; 177070), which are markers of erythrocyte maturation. Knockdown of ETO2 via small interfering RNA induced growth arrest and differentiation in human and mouse erythroid progenitors. Goardon et al. (2006) concluded that ETO2 is required for expansion of erythroid progenitors, but that it is dispensable for terminal maturation. They proposed that the stoichiometry of ETO2 with the TAL1 complex controls the transition from erythroid progenitor expansion to terminal differentiation.
Pimanda et al. (2007) identified Gata2 (137295), Tal1, and Fli1 (193067) and their enhancers as components of a gene regulatory network that operates during specification of mouse hematopoietic stem cells in the aorta-gonad-mesonephrose region and in fetal liver at midgestation.
Using human K562 and mouse MEL erythroleukemia cells and human Jurkat T-cell leukemia cells, Hu et al. (2009) showed that TAL1 interacted directly with the histone demethylase LSD1 (KDM1A; 609132) in 2 distinct HDAC1 (601241)-containing protein complexes. LSD1 inhibited TAL1-mediated reporter activity in a dose-dependent fashion, and this inhibition required the histone demethylase domain of LSD1. Tal1 associated with Lsd1 and demethylase activity in undifferentiated MEL cells, but not during the period when MEL cells became committed to differentiation. Association of Tal1 with the Lsd1 complex was recovered during late stages of differentiation. Tal1 bound 2 E-box GATA motifs in the proximal promoter of the gene encoding erythroid membrane protein P4.2 and targeted Lsd1 to the P4.2 promoter. Targeting of Lsd1 to the P4.2 promoter correlated with histone-3 (H3; see 602810) lys4 (H3K4) methylation at the P4.2 promoter. Following differentiation, Lsd1 dissociated from the promoter, permitting Tal1-mediated P4.2 transcription. Knockdown of Lsd1 via short hairpin RNA in MEL cells resulted in increased expression of P4.2 and Gata2 and an increase in dimethylated H3K4 at the P4.2 promoter. Hu et al. (2009) concluded that the H3K4 histone demethylase activity of LSD1 is partly responsible for the repressive activity of TAL1 and restricts TAL1 function in hematopoiesis.
TAL1 Enhancer
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements called superenhancers, which recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine-27 (H3K27ac). In a subset of T-ALL cases, Mansour et al. (2014) found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB (189990) transcription factor in a precise noncoding site, which creates a superenhancer 7.5 kb upstream of the TAL1 oncogene. Among 146 unselected pediatric primary T-ALL samples collected at diagnosis, 8 patients (5.5%) had heterozygous indels 2 to 18 bp in length that overlapped at the same clearly defined hotspot. Indels at this site were referred to as 'mutation of the TAL1 enhancer,' or MuTE. MYB binds to the new site introduced by MuTE and recruits its H3K27 acetylase-binding partner CBP (600140), as well as core components of a major leukemogenic transcriptional complex that contains RUNX1 (151385), GATA3 (131320), and TAL1 itself. Additionally, most endogenous superenhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in superenhancer initiation. Mansour et al. (2014) estimated that MuTE abnormalities account for about half of the cases with unexplained monoallelic overexpression of TAL1. Mansour et al. (2014) concluded that this study identified a genetic mechanism responsible for the generation of oncogenic superenhancers in malignant cells.
By sequence analysis, Finger et al. (1989) mapped the TCL5 gene to chromosome 1p32, whereas Begley et al. (1989) mapped the gene to chromosome 1p33. However, Finger et al. (1989) stated that the TCL5 gene is proximal to LMYC (MYCL1; 164850), supporting localization on chromosome 1p32 rather than 1p33.
Begley et al. (1991) mapped the mouse Scl gene to the central part of chromosome 4.
The pattern of SCL expression is highly conserved between mammals and zebrafish. Gottgens et al. (2002) isolated and characterized the zebrafish Scl locus and identified 3 neighboring genes, including Mupp1 (603785). This region spanned 68 kb and was the longest zebrafish genomic sequence available for comparison with mammalian, chicken, and pufferfish sequences. The Ier5 gene (607177) is located 5-prime of the Scl gene in zebrafish and is intronless in zebrafish, human, and mouse. The zebrafish gene homologous to human and mouse MAP17 (607178) lies 3-prime to SCL. MAP17 lies downstream of SCL in the human, mouse, and chicken genomes. The data showed conserved synteny between zebrafish and mammalian SCL and MAP17 loci, thus suggesting the likely genomic domain necessary for the conserved pattern of SCL expression.
Finger et al. (1989) analyzed a t(1;14)(p32;q11) chromosomal translocation in a lymphohemopoietic stem cell line derived from a patient with acute T-lymphoblastic leukemia (Kurtzberg et al., 1985). The chromosomal joining of 14 to 1p occurred at the T-cell receptor delta diversity (D-delta-2) segment, and the reciprocal joining on chromosome 14 occurred at the T-cell delta diversity segment D-delta-1. Involvement of delta diversity segments at the translocation junctions suggested that the translocation occurred during an attempt at delta-1/delta-2 joining in a stem cell. TCL5 is located at the segment of chromosome 1p32 adjacent to the chromosomal breakpoint. Finger et al. (1989) also demonstrated a rearrangement of the TCL5 gene in a human melanoma cell line carrying a deletion at 1p32.
The occurrence of 'biphenotypic' leukemias with lymphoid and myeloid characteristics and evidence of stem cell origin of myeloid, erythroid, megakaryocytic, and lymphoid lineages in chronic myeloid leukemia suggested that leukemias may arise from pluripotent hematopoietic cells. Begley et al. (1989) studied a leukemic stem cell line that was capable of differentiating into either myeloid or lymphoid cells and that carried a translocation t(1;14)(p33;q11). By means of molecular cloning and sequencing, they showed that as a consequence of the translocation an unusual fusion transcript was generated. The chromosome 1 region involved in the breakpoint contained SCL, whose transcriptional activity apparently occurred only in hematopoietic tissues.
In a review, Xia et al. (1991) stated that alteration of the TAL1 gene is the most common genetic lesion associated with T-ALL. Tumor-specific alterations of TAL1 arise by 1 of 2 distinct mechanisms. First, almost 25% of T-ALL patients exhibit a nearly precise 90-kb deletion of upstream sequences of 1 allele of the TAL1 locus. The site specificity of this deletion is apparently mediated by aberrant activity of the immunoglobulin recombinase. Second, an additional 3% of T-ALL patients harbor a translocation, t(1;14)(p34;q11), that transposes TAL1 from its normal location on chromosome 1 into the T-cell receptor alpha/delta-chain complex on chromosome 14. The chromosomal rearrangement that brings the SIL (181590) promoter into a relationship with the coding part of the SCL gene is another mechanism for generation of T-ALL (Aplan et al., 1992). Since structural lesions of TAL1 are commonly associated with T-ALL, TAL1 gene alterations are probably a critical factor in T-cell leukemogenesis.
Shivdasani et al. (1995) disrupted the tal1 gene in mice by homologous recombination in embryonic stem (ES) cells. The findings indicated that tal1 is essential for embryonic blood formation in vivo. With respect to embryonic erythropoiesis, tal1 deficiency resembled loss of the erythroid transcription factor Gata1 (305371) or the LIM protein Rbtn2 (180385). Profound reduction in myeloid cells cultured from tal1-null yolk sacs suggested a broader defect manifested at the myelo-erythroid or multipotential progenitor cell level.
Robb et al. (1995) created mice heterozygous for an scl-null mutation by targeting the gene in ES cells. When heterozygotes were intercrossed, homozygotes were not detected in newborn litters. Analysis at earlier time points demonstrated that homozygous null embryos died around embryonic day 9.5. These embryos were pale, edematous, and markedly growth retarded after embryonic day 8.75. Histologic studies showed complete absence of recognizable hematopoiesis in the yolk sac of homozygous embryos. Early organogenesis appeared to be otherwise normal. The results implicated SCL as a crucial regulator of early hematopoiesis.
Aplan et al. (1997) demonstrated that transgenic mice with inappropriately expressed scl protein, driven by sil regulatory elements, developed aggressive T-cell malignancies in collaboration with a misexpressed Lmo1 (186921) protein, thus recapitulating the situation seen in a subset of human T-cell ALL. Aplan et al. (1997) also demonstrated that inappropriately expressed scl could interfere with development of other tissues derived from mesoderm. Finally, Aplan et al. (1997) demonstrated that an scl construct lacking the scl transactivation domain collaborated with misexpressed Lmo1, demonstrating that the scl transactivation domain is dispensable for oncogenesis and supporting the hypothesis that the scl gene product exerts its oncogenic action through a dominant-negative mechanism.
Loss-of-function studies have shown that SCL is essential for the formation of hematopoietic stem cells, subsequent erythroid development, and yolk sac angiogenesis. SCL exhibits a highly conserved pattern of expression from mammals to teleost fish. To identify control and regulatory elements necessary for SCL expression in erythroid cells, Sinclair et al. (2002) studied scl -/- mice. They demonstrated that a 130-kb YAC containing the human SCL locus completely rescued the embryonic lethal phenotype of scl -/- mice. YAC-rescued scl -/- mice were born in appropriate mendelian ratios, were healthy and fertile, and exhibited no detectable abnormalities of yolk sac, fetal liver, or adult hematopoiesis. The human SCL protein can therefore substitute for its murine homolog. The results also demonstrated that the human SCL YAC contains the chromosome domain necessary to direct expression to the erythroid lineage and to all other tissues in which SCL performs a nonredundant essential function.
Mikkola et al. (2003) used conditional gene targeting in mice to assess whether Scl is required continuously for the identity and function of hematopoietic stem cells. They found that Scl was dispensable for hematopoietic stem cell engraftment, self-renewal, and differentiation into myeloid and lymphoid lineages; however, proper differentiation of erythroid and megakaryocytic precursors was dependent on Scl. Thus, they concluded that SCL is essential for genesis of hematopoietic stem cells, but its continued expression is not essential for hematopoietic stem cell functions. These findings contrast with lineage choice mechanisms, in which the identity of hematopoietic lineages requires continuous transcription factor expression.
Gene targeting studies have shown that the transcription factor SCL is critically important to embryonic hematopoiesis, but the early lethality of Scl-null mice precluded genetic analysis of this function in the adult. To perform genetic analysis of the function of Scl in adult Scl-null mouse hematopoiesis, Hall et al. (2003) generated a conditional knockout of SCL by using Cre/lox technology and an interferon-inducible Cre transgenic mouse. Deletion of SCL in adult mice perturbed megakaryopoiesis and erythropoiesis with the loss of early progenitor cells in both lineages. This led to a blunted response to the hematopoietic stress induced by polyinosinic-polycytidylic acid, with a persistently low platelet count and hematocrit compared with controls. In contrast, progenitors of granulocyte and macrophage lineages were not affected, even in the setting of stress. Immature progenitor cells (day 12 colony-forming unit spleen) with multilineage capacity were still present in the Scl-null bone marrow, but these progenitors had lost the capacity to generate erythroid and megakaryocyte cells, and colonies were composed of only myeloid cells. These results suggested the SCL is critical for megakaryopoiesis and erythropoiesis, but is dispensable for production of myeloid cells during adult hematopoiesis.
The Scl protein is an essential transcription factor during hematopoietic development in the mouse embryo. Kunisato et al. (2004) studied the role for Scl in adult mouse hematopoiesis. They performed bone marrow hematopoietic stem cell (HSC) transplantation and an in vitro HSC differentiation assay using retrovirally transduced HSCs with either wildtype or dominant-negative Scl. Transplantation experiments showed that Scl did not affect the long-term repopulating capacity of HSCs, but both wildtype and dominant-negative Scl increased the short-term contribution of the transduced HSCs in myeloid and lymphoid lineages, respectively. An in vitro single-cell assay using a fetal thymus organ culture system further demonstrated that wildtype Scl facilitated HSCs to differentiate into the myeloid lineage, but dominant-negative Scl facilitated HSCs to differentiate into the lymphoid lineage. Kunisato et al. (2004) concluded that upregulation or downregulation of SCL directs HSCs toward myeloid or lymphoid lineages, respectively, although SCL does not affect their long-term repopulating capacity.
Shultz et al. (1991) reported a mouse mutation called 'hairpatches' (Hpt). Newborn heterozygous mice could be recognized by 3 to 4 days of age by patches of lightly pigmented skin. A reduced number of hair follicles, abnormalities in hair follicle structure, and patchy absence of hair persisted throughout life. By 2 weeks of age, mice had abnormal hair follicle development accompanied by thickening of the epidermis, reduction in levels of subcutaneous fat, and dermal inflammation. Progressive glomerulosclerosis, resulting in renal failure, was accompanied by increases in glomerular mesangial matrix, deposition of immune complexes, and glomerular enlargement. Heterozygous mutant mice subsequently developed hypertrophy of the left ventricle of the heart, increased systolic blood pressure, and anemia. Shultz et al. (1991) mapped the mouse mutation to chromosome 4, 18 recombination units distal to 'brown' (see 115501) and near the alpha- and beta-interferon gene complex.
Hosur et al. (2013) determined that the mutation causing 'hairpatches' in the mouse was an intracisternal A particle (IAP) insertion in intron 4 of the Tal1 gene. Tal1 expression was significantly upregulated in affected tissues of the mutant mouse, including kidney, skin, and thymus. The Hpt mutation appeared to act in a dominant-negative manner, and Hosur et al. (2013) suggested that it promotes the overexpression of exons 4 and 5, which encode the DNA-binding domain of the protein.
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