Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation

Sasaki, Yutaka; Jensen, Christina T.; Karlsson, Stefán; Jacobsen, Sten Eirik W.

doi:10.1182/blood-2003-07-2277

Cited by 22 publications

(19 citation statements)

References 33 publications

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“…Mutant myeloid progenitor hyperproliferation would result from increased cyclin D2, in the absence of p16 Ink4a , as it occurs in Cyclin D2-transduced bone marrow cells (61). In turn, progressive accumulation of p16…”

Section: Discussionmentioning

confidence: 99%

Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion

Calés

Román-Trufero

Pavón

et al. 2008

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 99%

Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion

Calés

Román-Trufero

Pavón

et al. 2008

Molecular and Cellular Biology

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“…1 Furthermore, increased levels of cyclin D2 contribute to the proliferation and chemoresistance of malignant cells. [33][34][35][36][37] Therefore, these c-maf-independent inhibitors of cyclin D2 could be useful tools to better understand the regulation of cyclin D2. In addition, some of these molecules could be novel therapeutic agents for the treatment of multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

Mao

Stewart

Hurren

et al. 2007

Blood

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IntroductionMultiple myeloma appears to arise from initiating chromosomal translocations and duplications in postgerminal center plasma cells with subsequent secondary mutations contributing to disease progression. 1,2 Six unique myeloma variants can be identified by gene expression profiling with 3 of the 6 groups anchored by an initiating chromosome translocation. It is noteworthy that a unifying event of cyclin D dysregulation is identified in all subgroups. 1,2 One of the initiating chromosomal abnormalities in myeloma involves members of the Maf family of oncogenes. 1 Maf proteins are basic leucine zipper transcription factors in the AP1 family and regulate gene transcription by binding DNA sequences known as MAF responsive elements (MAREs). 3,4 Of the Maf family, c-maf was the first endogenous member identified and is probably the best characterized with respect to function. 5 Genes up-regulated by c-maf include cyclin D2, ␤-integrin 7, ARK 5 and CCR1, all of which are important in the pathogenesis of multiple myeloma. [6][7][8] c-maf is dysregulated in multiple myeloma. For example, approximately 25% of myeloma cell lines have a t(14;16) translocation. 6 In patients with myeloma, approximately 6% have a t(14;16) or t(14;20), translocations that juxtapose IgH with c-maf and its homolog mafB, respectively. 9,10 The frequency of c-maf overexpression in patients who lack the t(14;16) has varied from study to study, depending on the method to assess its overexpression and ranges from 5% to 50%. 6,11,12 In malignant cell lines, including multiple myeloma, overexpression of c-maf augments cell proliferation and increases tumor formation in xenograft models. 6,7 Conversely, inhibition of c-maf with dominant-negative constructs decreases cell proliferation, impairs adhesion to marrow stroma, and delays tumor growth. 6 Overexpression of c-maf is also clinically relevant in that patients with myeloma and the t(14;16) c-maf translocation have a shorter overall survival. 13 Although the functional importance of c-maf has been described, the mechanisms that govern its regulation have not been fully elucidated. Therefore, molecules that decrease c-maf and subsequently its downstream targets, particularly cyclin D2, could further our understanding of the regulation of c-maf. Improved understanding of c-maf will help develop therapies that target this protein.To this end, we developed a high-throughput chemical genomics screen to identify compounds that inhibit c-maf-dependent transactivation of the cyclin D2 promoter. With this assay, we screened libraries of off-patent drugs and chemicals and were surprised to identify glucocorticoids as inhibitors of c-mafdependent cyclin D2 transactivation. Subsequent studies demonstrated that glucocorticoids decrease c-maf protein by promoting its ubiquitination through the up-regulation of ubiquitin C mRNA. Thus, this chemical biology approach has provided insights into a novel mechanism of c-maf regulation. The publication costs of this article were defrayed in part by page charge ...

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“…32 Briefly, freshly isolated unfractionated BM or spleen cells were plated in methylcellulose (M3134; StemCell Technologies) supplemented with 20% FCS (Thermo Fisher Scientific), 1% L-glutamine, 1% penicillin/streptomycin (PAA), 0.1mM 2-mercaptoethanol (SigmaAldrich), human FLT3 ligand (FL, 10 ng/mL, PeproTech), mouse IL-3 (2 ng/mL; PeproTech), human granulocyte-colony stimulating factor (G-CSF, 10 ng/mL; Amgen), and mouse granulocyte-monocyte colony stimulating factor (5 ng/mL; Immunex) in 35-mm Petri dishes. Colonies (Ͼ 50 cells) were scored using an Olympus IX70 inverted microscope (Olympus) after 7 and 10 days of incubation at 37°C, 98% humidity, and 5% CO 2 .…”

Section: Myeloid Progenitor Assaysmentioning

confidence: 99%

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD–induced myeloproliferation

Kharazi

Mead

Mansour

et al. 2011

Blood

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IntroductionActivating mutations of growth factor receptors (GFRs) are frequent events in many tumor types. A common theme of such mutations is the acquisition of mutant allele specific imbalance (MASI) either because of copy number-neutral loss of heterozygosity or mutant allele amplification, particularly during disease progression. 1 For example, MASI affects epidermal GFR (EGFR) mutations in lung cancer and glioblastoma, 2 KIT mutations in gastrointestinal tumors, 3 and MPL mutations in myelofibrosis. 4 MASI of activated GFRs may accelerate disease through a simple gene-dosage effect, although it is also possible that loss of the wild-type (WT) protein enhances the impact of the mutant allele, for example, by enhancing formation of mutant homodimers. Although the impact of mutant GFR gene dosage has been modeled in vivo, [5][6][7][8] less is known about the impact of loss of the second WT allele. In the case of activating RET mutations in endocrine neoplasia, deletion of the WT allele occurs in connection with tumor progression, 9,10 although in a mouse model (Ret MEN2B ), hemizygous Ret mutations were not biologically distinct from heterozygous mutations. 11 Although many mutations confer a degree of ligand-independent GFR activation, in vitro studies often observe an additional impact of exogenous ligand. EGFR, 12 platelet-derived GFR, 13 and MET receptor tyrosine kinase mutations 14 are all dependent on their ligands for full transforming activity.FMS-like tyrosine kinase3 (FLT3) is a receptor tyrosine kinase expressed on normal hematopoietic multipotent progenitors 15 and acute leukemia blast cells. 16 Internal tandem duplications (ITDs) within the juxtamembrane domain of FLT3, inducing ligandindependent dimerization and constitutive signaling, occur in ϳ 25% of acute myeloid leukemia (AML). 16 FLT3-ITD is associated with high relapse rate and poor overall survival in AML. 16,17 As with other GFR mutations, MASI at the FLT3 locus in FLT3-ITD ϩ AML is associated with a particularly poor prognosis 18 and occurs because of copy number-neutral loss of heterozygosity with consequent ITD homozygosity. 19 Although MASI is uncommon at diagnosis (ϳ 15% of ITD ϩ cases), it is frequently observed at relapse. 20 Mice heterozygous for an ITD at the endogenous Flt3 locus develop chronic myeloproliferative disease (MPD) with expanded myeloid progenitor cells. 7,21 Importantly, ITD homozygosity results in a more severe MPD phenotype. 7 However, it remains unclear to what degree disease progression only reflects an ITD gene dosage effect and/or whether loss of the WT allele itself might accelerate the phenotype of heterozygous ITDs.Although ITDs clearly induce FLT3 ligand (FL)-independent autophosphorylation of FLT3, 16 addition of exogenous FL to FL-deficient ITD cell lines results in enhanced FLT3 receptor activation. 22 Furthermore, FL increases ITD-induced activation of STAT pathways in vitro, a mechanism proposed to mediate resistance to FLT3 inhibitors. 23 It has recently been suggested that increases in FL levels ...

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Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation

Cited by 22 publications

References 33 publications

Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion

Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD–induced myeloproliferation

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