HoxA9 induces insulin-like growth factor-1 receptor expression in B-lineage acute lymphoblastic leukemia

Whelan, Jarrett T.; Ludwig, Dale L.; Bertrand, F. E.

doi:10.1038/leu.2008.57

Cited by 33 publications

(24 citation statements)

References 42 publications

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“…reported that HOXA9 bound to the EphB4 promoter and stimulated its expression, resulting in an increase in endothelial cell migration [23]. Recently, Whelan et al indicated that HOXA9 overexpression induced the expression of another RTK member, the IGF-1 receptor, and subsequently promoted leukemic cell growth [22]. In the present study, we showed that the down-regulation of HOXA7 significantly reduced EGFR mRNA and protein expression in KGN cells.…”

Section: Discussionsupporting

confidence: 66%

“…The binding of EGF to EGFR leads to receptor dimerization, autophosphorylation and the activation of several downstream signaling pathways, such as the MAPK pathway and the PI3K/Akt pathway, which play roles in cell proliferation, motility, and survival [19]; these pathways have also been shown to contribute to the abnormal growth of several types of human cancers [20]. Recent reports have demonstrated that HOX genes play a role in the regulation of several RTK family members, including EGFR [21], IGF1-receptor [22], and Eph-receptor [23,24], during development. Moreover, EGFR activation has been reported to stimulate HOXA7 expression [25].…”

Section: Introductionmentioning

confidence: 99%

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Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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BackgroundHomeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited.MethodsTo determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay.ResultsOur results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect.ConclusionsOur present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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“…IGF-1 has been suggested to serve as B-cell leukaemia growth factor 21,45 ; here it was released from tumour-naive and tumourexposed Wt DCs, in vitro and in vivo. As expected, IGF-1 gene expression from tumour-naive C/EBPb À / À DCs was very low 46 , whereas lymphoma-conditioned DCs upregulated the IGF-1 gene message substantially.…”

Section: Discussionmentioning

confidence: 99%

“…While a complete identification of lymphomaderived factors that act on DC differentiation requires further investigation, we show that shifting the C/EBPb isoform ratio in favour of LAP/LAP* is consistent with the preferential expression of the pro-inflammatory cytokine IL-6 (ref. 63) and the growth factor IGF-1 in DCs 21,45,46 . Unexpectedly, CCL2 secretion from LIP knock-in DCs was similar to Wt DCs 64 , indicating that LIP might have a role in transcriptional activity beyond its function as a repressor.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

et al. 2014

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The capacity of dendritic cells (DCs) to regulate tumour-specific adaptive immune responses depends on their proper differentiation and homing status. Whereas DC-associated tumour-promoting functions are linked to T-cell tolerance and formation of an inflammatory milieu, DC-mediated direct effects on tumour growth have remained unexplored. Here we show that deletion of DCs substantially delays progression of Myc-driven lymphomas. Lymphoma-exposed DCs upregulate immunomodulatory cytokines, growth factors and the CCAAT/enhancer-binding protein b (C/EBPb). Moreover, Em-Myc lymphomas induce the preferential translation of the LAP/LAP* isoforms of C/EBPb. C/EBPb À/ À DCs are unresponsive to lymphoma-associated cytokine changes and in contrast to wild-type DCs, they are unable to mediate enhanced Em-Myc lymphoma cell survival. Antigen-specific T-cell proliferation in lymphoma-bearing mice is impaired; however, this immune suppression is reverted by the DC-restricted deletion of C/EBPb. Thus, we show that C/EBPb-controlled DC functions are critical steps for the creation of a lymphoma growth-promoting and -immunosuppressive niche.

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“…HoxA9 expression up-regulated Igf1r in a B-lineage acute lymphoblastic leukemia model. 43 Moreover, IGF-receptor signaling itself is important for HSC expansion, overexpression is associated with poor prognosis in multiple myeloma, and its ligand IGF-2 was present in the STIF medium. 20,[43][44][45] Whereas we clearly demonstrated a potent amplification of gammaretroviral insertional mutants during prolonged ex vivo cultivation, our subsequent experiments using the in vitro immortalization assay provided no evidence that the HSC-supportive STIF conditions lead to preferential survival of insertional mutants in vitro.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal fluctuation of lentiviral vector–transduced and expanded murine hematopoietic stem cells

Maetzig

Brugman

Bartels

et al. 2011

Blood

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Gene therapy has proven its potential to cure diseases of the hematopoietic system. However, severe adverse events observed in clinical trials have demanded improved gene-transfer conditions. Whereas progress has been made to reduce the genotoxicity of integrating gene vectors, the role of pretransplantation cultivation is less well investigated. We IntroductionHematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate into all cell types of the hematopoietic system. At physiologic steady-state conditions, only a limited number of HSCs are active at any given time, thus preserving a large fraction of quiescent cells as a reservoir for long-term regeneration. 1 As demonstrated by retroviral gene marking in transplanted mice or nonhuman primates, cycling HSCs are either periodically replaced (clonal succession), maintained as a constant minor pool (clonal maintenance), or follow a mixture of succession, maintenance, and cyclic reactivation (clonal fluctuation). [2][3][4][5] The latter depends on a rich HSC pool and thus requires optimized HSC culture and gene-transfer conditions to be maintained in gene-therapy protocols.Targeting HSCs with integrating gene vectors guarantees lifelong expression of the therapeutic transgene in all progeny cells, and has been effective for the cure of monogenetic diseases such as X-linked severe combined immunodeficiency, chronic granulomatous disease, adenosine deaminase deficiency, and adrenoleukodystrophy. [6][7][8][9] In the first 2 conditions, murine leukemia virus-derived gammaretroviral vector integrations in the vicinity of protooncogenes have led to premalignant clonal dominance and malignant transformation, 7,8 and similar observations have been made in murine models. 10,11 Some of the integration sites that mediate malignant transformation in humans (eg, EVI1, CCND2, and LMO2) can also be found in the Retroviral Tagged Cancer Gene Database, 12 a collection of integration sites of mouse tumors induced by replicating murine leukemia virus. Genes identified in multiple independent tumors are referred to as common insertion sites and are potentially linked to tumor initiation.To improve transduction of quiescent HSCs, HIV-1-derived lentiviral vectors have been developed and evaluated in preclinical and clinical studies. 9,13,14 In contrast to gammaretroviral vectors, which preferentially integrate close to transcription start sites, CpG islands, and DNaseI-hypersensitive sites, lentiviral vectors preferentially integrate within active transcription units. 15,16 In assays detecting transformed mutants, this pattern was found to be 3-to 10-fold safer than the gammaretroviral preferences, 17,18 most likely related to a reduced frequency of enhancer-mediated gene activation.The ability of lentiviral vectors to transduce nondividing cells allows for the use of short, "stemness"-preserving protocols for genetic modification of HSCs. 19 Interestingly, recently described cytokine cocktails such as STIF (stem cell factor [SCF], thrombopoietin ...

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HoxA9 induces insulin-like growth factor-1 receptor expression in B-lineage acute lymphoblastic leukemia

Cited by 33 publications

References 42 publications

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

Polyclonal fluctuation of lentiviral vector–transduced and expanded murine hematopoietic stem cells

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