The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells

Hou, Yu; Li, Wen; Sheng, Yue; Li, Liping; Huang, Yong; Zhang, Zhonghui; Zhu, Tongyu; Peace, David; Quigley, John G.; Wu, Weixin; Zhao, You Yang; Qian, Zhijian

doi:10.1038/ni.3204

Cited by 71 publications

(77 citation statements)

References 49 publications

(62 reference statements)

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“…Further encouraged by new evidence indicating that FOXM1 (1) drives tumor development and progression 15–19 by virtue of a complex mechanism that includes enhanced cell proliferation, migration and invasion 6 , regulation of the DNA damage response 20 and changes in the cancer epigenome 21 , (2) promotes cancer-cell resistance to ionizing radiation 22 and cytotoxic drugs 23 , (3) governs, in part, the survival and tissue-regenerating capacity of both normal hematopoietic stem cells 24 and malignant stem cell-like cells 25 , (4) links acquired resistance to cancer therapy with cancer stemness 26 and (5) owing to the development of specific small-molecule inhibitors 27 , may soon be targeted more effectively than possible in the past 28 , we here decided to evaluate whether FOXM1 might play an important but heretofore overlooked role in plasma cell myeloma.…”

Section: Introductionmentioning

confidence: 99%

FOXM1 is a therapeutic target for high-risk multiple myeloma

Yang

Sompallae

et al. 2015

Leukemia

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The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM datasets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive up-regulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was co-regulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these 3 genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1High subset of myeloma.

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Section: Introductionmentioning

confidence: 99%

FOXM1 is a therapeutic target for high-risk multiple myeloma

Yang

Sompallae

et al. 2015

Leukemia

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“…In particular, FOXM1 sustains the maintenance of hematopoietic stem cell (HSC) pool and b-catenin is essential for self-renewal of normal HSC and LSC of CML [Zhao et al, 2007;Hamilton et al, 2012;Hou et al, 2015]. In particular, FOXM1 sustains the maintenance of hematopoietic stem cell (HSC) pool and b-catenin is essential for self-renewal of normal HSC and LSC of CML [Zhao et al, 2007;Hamilton et al, 2012;Hou et al, 2015].…”

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confidence: 99%

FOXM1 Transcription Factor: A New Component of Chronic Myeloid Leukemia Stem Cell Proliferation Advantage

Mancini¹,

Castagnetti²,

Soverini³

et al. 2017

J of Cellular Biochemistry

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FOXM1 transcription factor is a central component of tumor initiation, growth, and progression due to its multiple effects on cell cycle, DNA repair, angiogenesis and invasion, chromatin, protein anabolism, and cell adhesion. Moreover, FOXM1 interacts with β-catenin promoting its nuclear import and transcriptional activation. Here, we show that FOXM1 is involved in the advantage of chronic myeloid leukemia hematopoiesis over the normal counterpart. FOXM1 hyper-activation associated with BCR-ABL1 results from phosphorylation by the fusion protein kinase-dependent activation of Polo-like kinase 1. FOXM1 phosphorylation lets its binding with β-catenin and β-catenin transcriptional activation, a key event for persistence of the leukemic stem cell compartment under tyrosine kinase inhibitor therapy. Polo-like kinase 1 inhibitor BI6727, already advanced for clinical use, breaks β-catenin interaction with FOXM1, hence hampering FOXM1 phosphorylation, β-catenin binding, nuclear import, and downstream signaling. In conclusion, our results support Polo-like kinase 1/FOXM1 axis as a complementary target to eradicate leukemic early progenitor/stem cell compartment in chronic myeloid leukemia. J. Cell. Biochem. 118: 3968-3975, 2017. © 2017 Wiley Periodicals, Inc.

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“…Flow cytometric analyses of subsets of HPCs and HSCs have been described in our previous studies(21,22). Dead cells were excluded by DAPI staining.…”

Section: Methodsmentioning

confidence: 99%

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Sheng

et al. 2017

Cancer Research

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Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the pre-leukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells (HSC) and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q).

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The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells

Cited by 71 publications

References 49 publications

FOXM1 is a therapeutic target for high-risk multiple myeloma

FOXM1 is a therapeutic target for high-risk multiple myeloma

FOXM1 Transcription Factor: A New Component of Chronic Myeloid Leukemia Stem Cell Proliferation Advantage

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

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