Hemgn is a direct transcriptional target of HOXB4 and induces expansion of murine myeloid progenitor cells

Jiang, Jie; Yu, Hui; Shou, Yan; Neale, Geoffrey; Zhou, Sheng; Lu, Taihe; Sorrentino, Brian P.

doi:10.1182/blood-2009-07-235341

Cited by 39 publications

(60 citation statements)

References 33 publications

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“…45 We find upregulation of HEMGN, (a transcription factor implicated in myeloid self-renewal 36 ), FHL2 (enhanced expression of which leads to enhanced cell cycle entry), FZD6 (shown to be involved in the pathologically reactivation of the Wnt/Fzd-mediated self-renewal signals that are enlisted during B-cell development and may be pathologically reactivated in the neoplastic transformation of mature B cells), and SETBP1 (overexpression of which promotes the self-renewal of myeloid progenitors [46][47][48] ). It is interesting that similar cellular processes are affected in the IKZF1 deleted cases, while none of the genes deregulated in IKZF1 deleted adult BCP-ALL are found deregulated in this pediatric IKZF1 deleted AML cohort.…”

Section: A B C D E Fmentioning

confidence: 99%

“…Interestingly, the gene most clearly up-regulated in both monosomy 7 and IKZF1-focal deleted samples was Hemogen (HEMGN), the overexpression of which has been described to induce expansion of myeloid progenitor cells in a murine model. 36 Other genes with known proleukemic functions in the top-correlating list are Four and a half LIM domains 2 (FHL2), Frizzled 6 (FZD6) and SET binding protein 1 (SETBP1) ( Figure 4E …”

Section: Similarity Between Gene Expression Profiles Of Monosomy 7 Anmentioning

confidence: 99%

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Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nby controlling transcriptional regulators, such as GATA1 and RUNX1. 18,20 Although IKZF1 is not required for the initial differentiation towards granulocytes and monocytes, IKZF1 represses differentiation of the basophilic granulocyte lineage and promotes early maturation and survival of the neutrophil granulocyte lineage. 17,21,22 In pediatric AML, monosomy 7 is found in only 4%-5% of patients. The 5-year OS and EFS of pediatric AML patients with monosomy 7 with or without additional cytogenetic or chromosomal aberrations are poor. 23 In adult AML, monosomy 7 is the most frequent single monosomy and has a similar poor 4-year OS as compared to other single autosomal monosomies. 24 Deletions of the short arm of chromosome 7, 7p (del7p) were recurrently found in adult de novo AML and secondary AML developed from myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). [25][26][27] Furthermore, 7p deletions were mapped to the IKZF1 locus and it was shown that loss of IKZF1 is acquired during the progression of MPN to secondairy AML, indicating that loss of IKZF1 contributes to the transformation from MPN to AML. 25 Together, these studies demonstrate that IKZF1 may play a role in myeloid differentiation and that loss of IKZF1 may contribute to myeloid oncogenesis. We, therefore, hypothesized that, in pediatric AML patients with monosomy 7, IKZF1 may be an important player. In this study, we analyzed the frequency of IKZF1 deletions in a pediatric AML cohort, and studied the difference in gene expression of cases with focal IKZF1 deletions, and cases with monosomy 7. Methods Patients' samplesSamples were provided by the Dutch Childhood Oncology Group (DCOG, the Netherlands), the AML-Berliner-FrankfurtMünster Study Group (Germany and Czech Republic), the SaintLouis Hospital (France), and the Royal Hospital for Sick Children (UK). Isolation of genomic DNA and total cellular RNA was performed using Trizol reagent. Each study group provided morphological and cytogenetic classification and clinical data. Institutional review board approval for these studies had been obtained in the participating centers. Detection of deletions and mutations of IKZF1Multiplex ligation-dependent probe amplification (MLPA) was performed using the p335-B1;ALL-IKZF1 kit (MRC Holland, Amsterdam, the Netherlands; data available at http: //www.mlpa.com). The data were analyzed with GeneMarker v. 1.85 (SoftGenetics, State College, Pennsylvania, USA). Data were normalized to reference probes and control samples. A deletion was defined as a peak ratio below 0.75; an amplification was defined as a peak ratio above 1.25.Array comparative genomic hybridization (Array-CGH) was performed using the human genome CGH Microarray 105K (Agilent Technologies, Santa Clara, California, USA) according to the manufacturer's protocol; data were analyzed with Genomic Workbench v. 5.0.14 (Agilent Technologies, Santa Clara, California, USA).Direct sequencing was used to analyze mutations or frameshif...

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Section: A B C D E Fmentioning

confidence: 99%

Section: Similarity Between Gene Expression Profiles Of Monosomy 7 Anmentioning

confidence: 99%

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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“…Our data indicate that cHEMGN acts as a transcription factor in the preSertoli cells to induce directly or indirectly SOX9 expression after sex determination. In the 5′-flanking region of mouse and human Hemgn/EDAG, binding sites for GATA1 (GATA binding protein 1) and HOXB4 (homeobox B4) (only reported in Hemgn) are present, and Hemgn/EDAG has been shown to be a direct transcriptional target of these genes in hematopoetic cells (22)(23)(24)(25). Future studies should determine the presence of a gonad-specific enhancer and transcription factors that mediate the gonadal expression of cHEMGN, as well as identify direct targets of cHEMGN.…”

Section: Expression In Masculinized Zw Gonads By Aromatase Inhibitormentioning

confidence: 99%

Chicken hemogen homolog is involved in the chicken-specific sex-determining mechanism

Nakata

Ishiguro

Aduma

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Using a comprehensive transcriptome analysis, a Z chromosomelinked chicken homolog of hemogen (cHEMGN) was identified and shown to be specifically involved in testis differentiation in early chicken embryos. Hemogen [Hemgn in mice, EDAG (erythroid differentiation-associated gene protein) in humans] was recently characterized as a hematopoietic tissue-specific gene encoding a transcription factor that regulates the proliferation and differentiation of hematopoietic cells in mammals. In chicken, cHEMGN was expressed not only in hematopoietic tissues but also in the early embryonic gonad of male chickens. The male-specific expression was identified in the nucleus of (pre)Sertoli cells after the sex determination period and before the expression of SOX9 (SRY-box 9). The expression of cHEMGN was induced in ZW embryonic gonads that were masculinized by aromatase inhibitor treatment. ZW embryos overexpressing cHEMGN, generated by infection with retrovirus carrying cHEMGN, showed masculinized gonads. These findings suggest that cHEMGN is a transcription factor specifically involved in chicken sex determination.bird | gonadal differentiation

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“…Little is known about the mechanism how HOXB4 expands HSCs and at meanwhile prevents leukemogenesis. 251,252 These earlier studies suggested that HOXB4 controls HSC or myeloid progenitors through multiple mechanisms such as apoptosis and symmetric division/proliferation. However, it is noticed that none of the previous studies focused on HOXB4 targets in primary primitive hematopoietic populations in vivo.…”

Section: Chapter 2 Identification Of Hoxb4 Transcriptional Target Gementioning

confidence: 99%

“…251 The helper-free recombinant retroviral vector supernatant was freshly collected from the GPE+86 producer cells and filtered through 0.45 µm pore filter for transduction.…”

Section: Retroviral Vector Preparationmentioning

confidence: 99%

Downregulation of Prdm16 Is Critical for HOXB4-mediated Benign HSC Expansion In Vivo

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Hemgn is a direct transcriptional target of HOXB4 and induces expansion of murine myeloid progenitor cells

Cited by 39 publications

References 33 publications

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Chicken hemogen homolog is involved in the chicken-specific sex-determining mechanism

Downregulation of Prdm16 Is Critical for HOXB4-mediated Benign HSC Expansion In Vivo

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