Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo

Yu, Hui; Neale, Geoffrey; Zhang, Hui; Lee, Han M.; Ma, Zhuo; Zhou, Sheng; Forget, Bernard G.; Sorrentino, Brian P.

doi:10.1182/blood-2013-10-534735

Cited by 20 publications

(19 citation statements)

References 44 publications

(50 reference statements)

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“…Expression of NID2 suppresses migration and inhibits metastasis by suppressing the EGFR/AKT and integrin/FAK/PLCγ pathways . HOXB4, as a hematopoietic transcription factor, downregulates the expression of Prdm16, which is a proto‐oncogene necessary for self‐renewal and maintenance of murine hematopoietic stem cells . The other eight frequently methylated candidates (CCDC181, DPP4, BEND4, CTNND2, ELMO1, SFMBT2, C1QL3, MIR129–2) confirmed in our study have also shown hypermethylation in other malignancies (Table ) .…”

Section: Discussionsupporting

confidence: 81%

“…32 HOXB4, as a hematopoietic transcription factor, downregulates the expression of Prdm16, which is a proto-oncogene necessary for self-renewal and maintenance of murine hematopoietic stem cells. 33 The other eight frequently methylated candidates (CCDC181, DPP4, BEND4, CTNND2, ELMO1, SFMBT2, C1QL3, MIR129-2) confirmed in our study have also shown hypermethylation in other malignancies (Table 1). [34][35][36][37][38][39][40][41][42] Among them, SFMBT2 and MIR129-2 have been shown to act as tumor suppressors.…”

Section: Discussionsupporting

confidence: 79%

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Discovery and development of differentially methylated regions in human papillomavirus‐related oropharyngeal squamous cell carcinoma

Ren

Gaykalova

Wang

et al. 2018

Intl Journal of Cancer

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Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 79%

Discovery and development of differentially methylated regions in human papillomavirus‐related oropharyngeal squamous cell carcinoma

Ren

Gaykalova

Wang

et al. 2018

Intl Journal of Cancer

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“…PGC1 and MED1) (data not shown), it is likely that the intrinsic activity of the PR domain is specifically required for tumor suppression function of PRDM16. Several previous studies have shown that overexpression of PR-less PRDM16S isoform, but not PRDM16, is leukemogenic: 1) leukemogenic translocation in AMLs mostly involves PRDM16S, but not full length PRDM16 (Quentin et al, 2011; Shimizu et al, 2000); 2) PRDM16S is selectively overexpressed in adult T cell leukemia (Yoshida et al, 2004); 3) aberrant expression of PRDM16S by retroviral insertion promotes immortalization of murine bone marrow progenitors and blocks granulocytic differentiation (Du et al, 2005a; Nishikata et al, 2003); 4) overexpression of Prdm16S in p53 null bone marrow cells induces AML with full penetrance (Shing et al, 2007); and 5) overexpression of both Prdm16S and Hoxb4 led to myeloid expansion and leukemia (Yu et al, 2014). These studies suggest that loss of the PR-domain is compatible with leukemogenesis.…”

Section: Discussionmentioning

confidence: 99%

PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity

et al. 2016

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SUMMARY PRDM16 is a transcription cofactor that plays critical roles in development of brown adipose tissue (BAT) as well as maintenance of adult hematopoietic and neural stem cells. Here we report that PRDM16 is a histone H3 K4 methyltransferase on chromatin. Mutation in the N-terminal PR-domain of PRDM16 completely abolishes the intrinsic enzymatic activity of PRDM16. We show that the methyltransferase activity of PRDM16 is required for specific suppression of MLL leukemogenesis both in vitro and in vivo. Mechanistic studies show that PRDM16 directly activates the SNAG family transcription factor GFI1b, which in turn down regulates the HOXA gene cluster. Knockdown GFI1b represses PRDM16-mediated tumor suppression while GFI1b overexpression mimics PRDM16 overexpression. In further support of the tumor suppressor function of PRDM16, silencing PRDM16 by DNA methylation is concomitant with MLL-AF9 induced leukemic transformation. Taken together, our study reveals a previously uncharacterized function of PRDM16 that depends on its PR-domain activity.

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“…IRX1 activates HOXB4 which is on the apex of an important stem cell program that allows the maintenance and expansion of stem cells [45–49]. It is highly likely that this mechanism is necessary to induce and maintain leukemic stem cells.…”

Section: Discussionmentioning

confidence: 99%

The IRX1/HOXA connection: insights into a novel t(4;11)- specific cancer mechanism

2016

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One hallmark of MLL-r leukemia is the highly specific gene expression signature indicative for commonly deregulated target genes. An usual read-out for this transcriptional deregulation is the HOXA gene cluster, where upregulated HOXA genes are detected in MLL-r AML and ALL patients. In case of t(4;11) leukemia, this simple picture becomes challenged, because these patients separate into HOXA hi -and HOXA lo -patients. HOXA lo -patients showed a reduced HOXA gene transcription, but instead overexpressed the homeobox gene IRX1. This transcriptional pattern was associated with a higher relapse rate and worse outcome. Here, we demonstrate that IRX1 binds to the MLL-AF4 complex at target gene promotors and counteract its promotor activating function. In addition, IRX1 induces transcription of HOXB4 and EGR family members. HOXB4 is usually a downstream target of c-KIT, WNT and TPO signaling pathways and necessary for maintaining and expanding in hematopoietic stem cells. EGR proteins control a p21-dependent quiescence program for hematopoietic stem cells. Both IRX1-dependend actions may help t(4;11) leukemia cells to establish a stem cell compartment. We also demonstrate that HDACi administration is functionally interfering with IRX1 and MLL-AF4, a finding which could help to improve new treatment options for t(4;11) patients.

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Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo

Abstract: Key Points HOXB4 induces stable gene expression changes in transplanted HSCs that drive balanced self-renewal and differentiation divisions. Marked downregulation of Prdm16 occurs concurrently with HOXB4-mediated HSC expansion and functions to prevent leukemia in vivo.

Cited by 20 publications

References 44 publications

Discovery and development of differentially methylated regions in human papillomavirus‐related oropharyngeal squamous cell carcinoma

Discovery and development of differentially methylated regions in human papillomavirus‐related oropharyngeal squamous cell carcinoma

PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity

The IRX1/HOXA connection: insights into a novel t(4;11)- specific cancer mechanism

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