Other entities represented in this entry:
HGNC Approved Gene Symbol: HLF
Cytogenetic location: 17q22 Genomic coordinates (GRCh38) : 17:55,264,960-55,325,187 (from NCBI)
Inaba et al. (1992) showed that a t(17;19) chromosomal translocation in early B-lineage acute leukemia resulted in chimeric transcripts that contained sequences from the E2A basic helix-loop-helix (bHLH) transcription factor gene (E2A; 147141) on chromosome 19, fused to sequences from a novel gene on chromosome 17 that encodes a hepatic leukemia factor (HLF). The chimeric protein consisted of the amino-terminal transactivation domain of E2A linked to the carboxyl-terminal basic region-leucine zipper domain of HLF. By screening a hepatoma cell line cDNA library, Inaba et al. (1992) isolated cDNAs encoding HLF. The predicted HLF protein contains 295 amino acids and has a calculated molecular mass of 33.3 kD. In vitro transcription and translation yielded a protein of about 43 kD. HLF was normally expressed in liver and kidney, but not in lymphoid cells, and was found to be closely related to the leucine zipper-containing transcription factors DBP (albumin D box-binding protein; 124097) and TEF (thyrotroph embryonic factor; 188595), which regulate developmental stage-specific gene expression. DBP is responsible for high, tissue-specific expression of albumin in fully differentiated hepatocytes, is expressed by adult but not fetal liver cells, and is rapidly down-regulated in proliferating hepatocytes. TEF is expressed by thyrotrophs in the anterior pituitary during embryonic development. It binds to and transactivates the thyroid-stimulating hormone beta promoter, contains an NH2-terminal activator domain, and forms homodimers and heterodimers with DBP through its leucine zipper region.
Hunger et al. (1992) also cloned HLF and determined that it is a member of the PAR bZIP (proline and acidic amino acid-rich basic leucine zipper) transcription factor family. The 295-amino acid HLF protein has a C-terminal PAR domain and a bZIP region. The C-terminal 138 amino acids of HLF share 73% identity with the corresponding region of TEF and 68% identity with the corresponding region of DBP. Northern blot analysis detected abundant HLF expression in adult liver and in a hepatocellular carcinoma cell line, with lower levels in adult kidney and lung. Of several fetal tissues examined, HLF was expressed only in fetal liver, at a level significantly lower than that seen in adult liver. No expression was detected in normal peripheral blood mononuclear cells or in any hematolymphoid cell line examined. Hunger et al. (1992) confirmed that HLF is a DNA-binding protein. HLF bound DNA specifically as a homodimer or as a heterodimer with other PAR factors. Hunger et al. (1992) also found that the E2A-HLF fusion protein resulting from the t(17;19) translocation contained structural alterations that impaired its ability to bind DNA as a homodimer compared with wildtype HLF. However, E2A-HLF could bind DNA as a heterodimer with other PAR proteins.
Hepatic leukemia factor controls apoptosis of serotonergic neurons in Caenorhabditis elegans. Ectopic expression of HLF as the E2A-HLF fusion protein promotes malignancy in acute lymphoblastic leukemia by interfering with apoptosis. While HLF has been linked to malignancies of the lymphoid system, it is not normally expressed in these cells. Rather, HLF transcripts are detected in the liver, kidney, lung, and adult nervous system by Northern blot analysis. To study the distribution and function of HLF in the adult and developing mammalian nervous system, Hitzler et al. (1999) cloned mouse Hlf and studied its expression by in situ hybridization. During embryonic brain development, Hlf expression was restricted to the anterior pituitary and meninges. By early postnatal life it was highly expressed in somatosensory cortex, thalamic nuclei, and structures arising from ectodermal placodes. Subsequently, its expression increased in the CNS and was found throughout the brain by adulthood. Hitzler et al. (1999) interpreted these data to suggest that HLF plays a role in the function of differentiated neurons in the adult nervous system rather than programmed cell death.
Gachon et al. (2004) stated that the expression of all 3 PAR bZIP transcription factors, HLF, TEF, and DBP, show high-amplitude circadian expression in the suprachiasmatic nucleus, the master circadian pacemaker in mammals. However, they are expressed at nearly invariable levels in most brain regions, in which clock gene expression only cycles with low amplitude. RT-PCR of mouse tissues demonstrated that all 3 PAR bZIP transcription factors show higher amplitude circadian cycles of expression in liver than in whole brain. Only 1 of 3 promoters of mouse liver Hlf initiated circadian transcription. Genes controlled by the PAR bZIP transcription factors showed similar circadian cycles of expression, with higher amplitude in mouse liver.
Using Hlf reporter mouse embryos, Yokomizo et al. (2019) found that Hlf was expressed in fetal liver hematopoietic stem cells (HSCs) and hematopoietic clusters in dorsal aorta, but not in erythromyeloid progenitors (EMPs) or yolk sac hematopoietic clusters before embryonic day 9.5. Hlf expression increased during HSC development. RNA sequencing analysis confirmed that HSC-specifying genes were activated in Hlf-expressing hematopoietic clusters, and Evi1 (MECOM; 165215) was involved in maturation of preHSCs into HSCs.
Hunger (1996) reviewed clinical features and the molecular pathogenesis of acute lymphoblastic leukemia (ALL) caused by chromosomal translocations involving the E2A gene. E2A proteins play an indispensable role in B-cell lymphopoiesis. The pathogenesis of a subset of B-precursor ALLs involves replacement of the bHLH regions of the E2A protein with heterologous DNA-binding domains.
To investigate the biologic role of the E2A/HLF fusion gene, Honda et al. (1999) generated transgenic mice expressing E2A/HLF in the lymphoid lineage. The transgenic mice exhibited abnormal development in the thymus and spleen and were susceptible to infection. The thymus contained small numbers of thymocytes and showed a high population of thymocytes undergoing apoptosis. The spleen exhibited a marked reduction in lymphocytes, and studies showed that B-cell maturation was blocked at a very early developmental stage. Several transgenic mice developed acute leukemia, classified as T-ALL.
Smith et al. (1999) likewise studied the function of the fusion gene in transgenic mice. Approximately 60% of E2A/HLF mice developed lymphoid malignancies with a mean latency of 10 months. Tumors were monoclonal, consistent with the requirement for secondary genetic events. Smith et al. (1999) concluded that the fusion gene disrupts the differentiation of T-lymphoid precursors in vivo, leading to profound postnatal thymic depletion and rendering B- and T-cell progenitors susceptible to malignant transformation.
Kurosawa et al. (1999) found that E2A/HLF upregulated expression of SRPUL (SRPX2; 300642) and annexin-8 (ANXA8; 602396) in pro-B cells. Transfection of a human myeloid leukemia cell line with E2A/HLF induced expression of ANXA8, but not SRPUL. E2A/HLF protected mouse pro-B cells from apoptosis caused by IL3 (147740) deprivation, but neither ANXA8 or SRPUL could block apoptosis, suggesting that they are not involved in malignant transformation.
Using representational difference analysis, Dang et al. (2001) found that the E2A/HLF fusion protein upregulated expression of several groucho-related genes (GRGs), including Grg2 and Grg6 (TLE6; 612399), following expression in a mouse pro-B cell line. A mutant E2A/HLF protein lacking DNA-binding activity also stimulated expression of GRGs. Among the transcription factors that interact with GRG proteins, only Runx1 (151385) was appreciably downregulated by E2A/HLF.
Gachon et al. (2004) found that mice homozygous for Hlf and Tef mutant alleles were morphologically normal and fertile. Animals devoid of any 2 or 3 PAR bZIP transcription factors were anatomically normal and fertile, but those lacking all 3 had dramatically shortened life span. Within the first month after birth, homozygous triple-knockout mice developed spontaneous epilepsy characterized by myoclonic, tonic-clonic, and possibly absence seizures, in addition to audiogenic seizure susceptibility. PAR bZIP-deficient mice show decreased brain levels of pyridoxal-5-phosphate, serotonin, and dopamine. Gachon et al. (2004) concluded that the expression of some clock-controlled genes may have to remain within narrow limits in the brain and undergo only low-amplitude cycles of expression in most brain regions.
Dang, J., Inukai, T., Kurosawa, H., Goi, K., Inaba, T., Lenny, N. T., Downing, J. R., Stifani, S., Look, A. T. The E2A-HLF oncoprotein activates Groucho-related genes and suppresses Runx1. Molec. Cell. Biol. 21: 5935-5945, 2001. [PubMed: 11486032] [Full Text: https://doi.org/10.1128/MCB.21.17.5935-5945.2001]
Gachon, F., Fonjallaz, P., Damiola, F., Gos, P., Kodama, T., Zakany, J., Duboule, D., Petit, B., Tafti, M., Schibler, U. The loss of circadian PAR bZIP transcription factors results in epilepsy. Genes Dev. 18: 1397-1412, 2004. [PubMed: 15175240] [Full Text: https://doi.org/10.1101/gad.301404]
Hitzler, J. K., Soares, H. D., Drolet, D. W., Inaba, T., O'Connel, S., Rosenfeld, M. G., Morgan, J. I., Look, A. T. Expression patterns of the hepatic leukemia factor gene in the nervous system of developing and adult mice. Brain Res. 820: 1-11, 1999. [PubMed: 10023025] [Full Text: https://doi.org/10.1016/s0006-8993(98)00999-8]
Honda, H., Inaba, T., Suzuki, T., Oda, H., Ebihara, Y., Tsuiji, K., Nakahata, T., Ishikawa, T., Yazaki, Y., Hirai, H. Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia. Blood 93: 2780-2790, 1999. [PubMed: 10216071]
Hunger, S. P., Ohyashiki, K., Toyama, K., Cleary, M. L. Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Genes Dev. 6: 1608-1620, 1992. [PubMed: 1516826] [Full Text: https://doi.org/10.1101/gad.6.9.1608]
Hunger, S. P. Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 87: 1211-1224, 1996. [PubMed: 8608207]
Inaba, T., Roberts, W. M., Shapiro, L. H., Jolly, K. W., Raimondi, S. C., Smith, S. D., Look, A. T. Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Science 257: 531-534, 1992. [PubMed: 1386162] [Full Text: https://doi.org/10.1126/science.1386162]
Kurosawa, H., Goi, K., Inukai, T., Inaba, T., Chang, K.-S., Shinjyo, T., Rakestraw, K. M., Naeve, C. W., Look, A. T. Two candidate downstream target genes for E2A-HLF. Blood 93: 321-332, 1999. [PubMed: 9864177]
Smith, K. S., Rhee, J. W., Naumovski, L., Cleary, M. L. Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice. Molec. Cell. Biol. 19: 4443-4451, 1999. [PubMed: 10330184] [Full Text: https://doi.org/10.1128/MCB.19.6.4443]
Yokomizo, T., Watanabe, N., Umemoto, T., Matsuo, J., Harai, R., Kihara, Y., Nakamura, E., Tada, N., Sato, T., Takaku, T., Shimono, A., Takizawa, H., Nakagata, N., Mori, S., Kurokawa, M., Tenen, D. G., Osato, M., Suda, T., Komatsu, N. Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors. J. Exp. Med. 216: 1599-1614, 2019. [PubMed: 31076455] [Full Text: https://doi.org/10.1084/jem.20181399]