PBX3 is an important cofactor of HOXA9 in leukemogenesis

Li, Zejuan; Zhang, Zhe; Li, Yuanyuan; Arnovitz, Stephen; Chen, Ping; Huang, Hao; Jiang, Xi; Hong, Gia Ming; Kunjamma, Rejani B.; Ren, Haomin; He, Chunjiang; Wang, Chong Zhi; Elkahloun, Abdel G.; Valk, Peter J.M.; Döhner, Konstanze; Neilly, Mary Beth; Bullinger, Lars; Delwel, Ruud; Löwenberg, Bob; Liu, Paul P.; Morgan, Richard; Rowley, Janet D.; Yuan, Chun Su; Chen, Jianjun

doi:10.1182/blood-2012-07-442004

Cited by 123 publications

(143 citation statements)

References 47 publications

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“…It appears to be the most critical member of PBX family contributing to leukaemogenesis by serving as a cofactor of other homeodomain proteins such as HOX and MEIS 34,35 to control gene expression, and has been identified as a direct target of let-7c, miR-181a/miR-181b, to function in colorectal cancer metastasis and leukaemogenesis, respectively 36,37 . Hence, PBX3 was chosen to validate further whether it was directly targeted by the four miRNAs to regulate a2d1 þ HCC TICs.…”

Section: Resultsmentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

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Section: Resultsmentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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“…17 Interest in Pbx proteins as Hox cofactors was rekindled with the discovery that another Pbx family member, Pbx3, cooperated with Hoxa9 in experimental leukemogenesis and that knock-down of Pbx3 could impair transformation induced by Hoxa9. 18,19 In a clinical setting PBX3 expression was an independent predictor of poor survival in leukemia patients and the presence of PBX3 was well correlated with HOX status within leukemic cells. Yet, the molecular mechanism behind these in vivo observations was not investigated further.…”

Section: Introductionmentioning

confidence: 99%

Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia

García-Cuéllar¹,

Steger²,

E³

et al. 2015

Haematologica

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Hox homeobox transcription factors drive leukemogenesis efficiently only in the presence of Meis or Pbx proteins. Here we show that Pbx3 and Meis1 need to dimerize to support Hox-induced leukemia and we analyze the molecular details of this cooperation. In the absence of Pbx3, Meis1 was highly unstable. As shown by a deletion analysis Meis1 degradation was contingent on a motif coinciding with the Pbx-binding domain. Either deletion of this sequence or binding to Pbx3 prolonged the half-life of Meis1 by preventing its ubiquitination. Meis1 break-down could also be blocked by inhibition of the ubiquitin proteasome system, indicating tight post-transcriptional control. In addition, Meis1 and Pbx3 cooperated genetically as overexpression of Pbx3 induced endogenous Meis1 transcription. These functional interactions translated into in vivo activity. Blocking Meis1/Pbx3 dimerization abrogated the ability to enhance proliferation and colony-forming cell numbers in primary cells transformed by Hoxa9. Furthermore, expression of Meis1 target genes Flt3 and Trib2 was dependent on Pbx3/Meis1 dimerization. This correlated with the requirement of Meis1 to bind Pbx3 in order to form high affinity DNA/Hoxa9/Meis1/Pbx3 complexes in vitro. Finally, kinetics and severity of disease in transplantation assays indicated that Pbx3/Meis1 dimers are rate-limiting factors for Hoxa9-induced leukemia. Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemiaMaria-Paz Garcia-Cuellar, Julia Steger, Elisa Füller, Katrin Hetzner, and Robert K. Slany Department of Genetics, Friedrich-Alexander-University, Erlangen, Germany ABSTRACT ments the ability of Meis1 to support Hox-mediated leukemogenesis. We demonstrate that Pbx3 protects Meis1 from proteasomal degradation. Additionally, Pbx3 increases Meis1 affinity for Hoxa9 and it induces endogenous Meis1 transcription. MethodsPlasmids, retroviral constructs, antibodies and cell culture

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“…HOXA9, MEIS1, and PBX3 are the three most well-studied critical oncogenic targets of MLL fusions (36,39,(42)(43)(44)(45)(46)(47)(48). Interestingly, previous genomewide ChIP-seq or ChIP-chip assays of Tet1 in mESCs suggest that Hoxa9, Meis1, and Pbx3 are potential direct target genes of Tet1 in mESCs (14)(15)(16) (Fig.…”

Section: Tet1 Is a Direct Target Gene Of Mll And Particularly Mll-fusionmentioning

confidence: 99%

“…Those were performed as described previously (41,47,48,50) with some modifications. See Table S3 for primer sequences for the chromatin immunoprecipitation (ChIP) assay.…”

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confidence: 99%

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

Huang¹,

Jiang²,

Li³

et al. 2013

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

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The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent downregulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/ Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.

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PBX3 is an important cofactor of HOXA9 in leukemogenesis

Cited by 123 publications

References 47 publications

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

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