Over‐expression of short isoforms of Helios in patients with adult T‐cell leukaemia/lymphoma

Fujii, Keiko; Ishimaru, Fumihiko; Nakase, Koichi; Tabayashi, Takayuki; Kozuka, Teruhiko; Naoki, Kyoko; Miyahara, Masayuki; Toki, H; Kitajima, Koichi; Harada, Mine; Tanimoto, Mitsune

doi:10.1046/j.1365-2141.2003.04216.x

Cited by 19 publications

(16 citation statements)

References 18 publications

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“…IKZF2 encodes Helios, a T cell-restricted Ikaros-family transcription factor, and is expressed in various PTCLs. [42][43][44][45] IKZF2 was expressed similarly in TCL75 and other cases, whereas ERBB4 was expressed only in TCL75 exons 2 to 28 encoded by IKZF2-ERBB4, which includes the ERBB4 kinase domain (supplemental Figure D-E). Thus, the fusion, which contains only exons 1 to 2 of IKZF2, co-opts the IKZF2 promoter for expression.…”

Section: Mpseq/rnaseq Identifies Novel Kinase Fusions In Ptcl Nosmentioning

confidence: 99%

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Boddicker¹,

Razidlo

Dasari

et al. 2016

Blood

100

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Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a “wastebasket” category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies.

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Section: Mpseq/rnaseq Identifies Novel Kinase Fusions In Ptcl Nosmentioning

confidence: 99%

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Boddicker¹,

Razidlo

Dasari

et al. 2016

Blood

100

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“…[19][20][21][22][23] Expression of non-DNA-binding isoforms of Helios have been noted in adult cases of T-cell ALL. [24][25][26] To date, a loss-of-function mutation in the Helios gene has not been described so it remains unclear as to whether Helios is also functioning as a tumor suppressor in lymphocytes in a manner analogous to Ikaros and Aiolos.In addition to the function of Ikaros family members in the regulation of lymphoproliferation, Ikaros has also been shown to regulate early developmental decisions within the hematolymphoid system. Mice homozygous for the Ikaros DN mutation died soon For personal use only.…”

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confidence: 99%

Expression of a non–DNA-binding isoform of Helios induces T-cell lymphoma in mice

Zhang

Swindle

Bates

et al. 2006

Blood

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IntroductionThe Ikaros family of zinc-finger DNA-binding proteins plays a vital role in the generation of all lymphoid-derived hematopoietic cell lineages. 1,2 Members of this highly conserved family of proteins that are expressed predominantly in lymphoid cells include Ikaros, Helios, and Aiolos. Each protein is highly homologous throughout an N-terminal DNA-binding domain comprised of 4 Krüppel-like zinc-finger domains of the C 2 H 2 type. Each protein also contains a C-terminal region comprised of 2 zinc-finger domains that mediate dimerization between family members. [3][4][5][6][7][8][9][10] Extensive alternative mRNA splicing of exons within the DNAbinding domain of Ikaros, Helios, and Aiolos results in the expression of multiple, functionally distinct isoforms of each protein that are differentially expressed in unique subsets of hematopoietic cells. [11][12][13][14] All mRNA splice variants characterized to date retain the C-terminal multimerization domain, therefore permitting the association of isoforms that lack the DNA-binding domain with isoforms that retain the ability to bind DNA. Association of non-DNA-binding isoforms of Ikaros with fulllength Ikaros proteins has been shown to inhibit DNA-binding and transactivation potential of Ikaros in in vitro assays. 5 Inhibition of Ikaros activity by non-DNA-binding Ikaros isoforms is further supported by the phenotype of animals with a targeted deletion of exons encoding the Ikaros DNA-binding domain (Ikaros DN) 1 and in animals with a point mutation in one of the zinc-finger exons that disrupts DNA binding without affecting multimerization. 15 Heterozygous Ikaros DN animals express similar levels of the dominant-negative and wild-type Ikaros alleles and develop T-cell lymphoma and leukemia with 100% penetrance soon after 3 months of age. 16 Prior to the development of lymphoma, thymocytes within the heterozygous animals displayed increased proliferative responses to T-cell receptor (TCR)-mediated signals, which suggests that non-DNA-binding isoforms of Ikaros suppress the antiproliferative activity of full-length Ikaros isoforms during thymocyte development. Lymphoma in the animals was characterized by a loss of heterozygosity at the Ikaros locus, which indicates that the balance of different Ikaros mRNA splice variants is crucial for normal homeostasis of developing thymocytes. The increased proliferative response of B lymphocytes to B-cell receptor stimulation observed in animals with a targeted disruption of the Aiolos DNA-binding domain 17 or in transgenic animals that express full-length Helios in the B-cell lineage 18 suggests that higher order complexes comprised of Ikaros family members function as key regulators of proliferative responses in both T and B lymphocytes.Consistent with the role of Ikaros family members as tumor suppressor genes in lymphocytes are observations of increased expression of non-DNA-binding isoforms of Ikaros, Aiolos, and Helios in cases of acute lymphocytic leukemia (ALL). An increase in non-DNA-binding isoforms of Ikaro...

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“…The presence of the alternative splice Helios variants was first revealed in research studies utilizing the primary leukemic cells from patients with newly diagnosed ALL (12)(13)(14). In this study, we observed that dominant-negative Helios-Δ326-1431 potentially induces the expression of several oncogenes.…”

Section: Discussionmentioning

confidence: 58%

“…In contrast, the T-cell malignancies were only observed in the gene-targeted mice of Ikaros (30). The related gene Helios has been shown to frequently exhibit multiple dominant-negative isoforms in patients with T-cell acute leukemia (6,(11)(12)(13)(14). In the mouse model, the overexpression of the artificial dominant-negative Helios isoform leads to increased T-cell proliferation, as well as the development of T-cell lymphomas (31).…”

Section: Discussionmentioning

confidence: 99%

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Role of a non-canonical splice variant of the Helios gene in the differentiation of acute lymphoblastic leukemic T cells

Liu

et al. 2018

Oncol Lett

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Abstract. T-cell acute lymphoblastic leukemia is a hematopoietic malignant disease, which arises from a genetic defect in the T-cell maturation signaling pathway. As a result, it is necessary to identify the molecules that impact T-cell development and control lymphoid-lineage malignancy. The present study utilized Jurkat T lymphoblastic cells as a well-established approach for the investigation into the function of the non-canonical alternative splice variant of Helios for the in vitro study of T-cell differentiation and leukemogenesis. In the present study, the Jurkat T-cell lines with stable overexpression of the wild-type (Helios-1) or the non-canonical short isoform (Helios-Δ326-1431), were established. RNA microarray, reverse transcription-quantitative polymerase chain reaction and flow cytometry were used to assess changes in the gene expression profiles and to monitor the cell surface markers during T-cell differentiation. Multiple genes associated with T-cell differentiation and leukemogenesis were identified as being either activated or suppressed. In addition, the results indicated that the stable overexpression of the Helios isoforms stimulated the differentiation pathway of the T-lineage lymphoblastic cells. Therefore, these results suggest that full-length Helios-1 has a tumor suppressor-like and immunomodulatory role, in contrast to the oncogenic function of the non-canonical short isoform

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Over‐expression of short isoforms of Helios in patients with adult T‐cell leukaemia/lymphoma

Cited by 19 publications

References 18 publications

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Expression of a non–DNA-binding isoform of Helios induces T-cell lymphoma in mice

Role of a non-canonical splice variant of the Helios gene in the differentiation of acute lymphoblastic leukemic T cells

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