FOXM1 is a therapeutic target in high-risk multiple myeloma

Gu, Chunyan; Yang, Ye; Holman, Carol J.; Xu, Hui; Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

doi:10.1016/j.clml.2015.07.499

Cited by 4 publications

(7 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, inhibition of these TFs may represent a rational therapeutic approach to revert aberrant chromatin activation in MM. This hypothesis is supported by previous publications indicating that IRF4 or FOXM1 inhibition induces cell death and influences the proliferation in MM cell lines, although efficient strategies to block these TF in MM patients are still missing (Shaffer et al 2008; Morelli et al 2015; Gu et al 2016).…”

Section: Discussionsupporting

confidence: 81%

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Ordóñez

Kulis

Russiñol

et al. 2019

Preprint

View full text Add to dashboard Cite

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting co-regulated adjacent genes. Among target genes upregulated by this process, we found members of the NOTCH, NFkB, mTOR1 signaling and p53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status, and in addition identified PRDM5 as a novel essential gene for MM. Collectively our data indicates that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

show abstract

Section: Discussionsupporting

confidence: 81%

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Ordóñez

Kulis

Russiñol

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…[8][9][10] A previous study also reported that FoxM1null hepatocytes were highly resistant to developing diethylnitrosamine/phenobarbital-induced HCC in mice. 11 Furthermore, several publications, including ours, reported that FoxM1 was highly expressed in human cancers, such as intrahepatic cholangiocarcinomas, 12 basal cell carcinomas, 13 infiltrating ductal breast carcinomas, 14 anaplastic astrocytomas and glioblastomas, 15 colorectal cancer, 16 leukemia, 17,18 ovarian cancer, 19 prostate cancer, [20][21][22] gastric cancer, 23,24 and many human cancer cell lines. 25 In addition, recently, pharmacological approaches to inhibit FoxM1 expression in animal models of cancers have been reported, 17,18,22 suggesting that drugs targeting FoxM1 may open new avenues in cancer therapy.…”

Section: Introductionmentioning

confidence: 72%

“…Furthermore, several publications, including ours, reported that FoxM1 was highly expressed in human cancers, such as intrahepatic cholangiocarcinomas, basal cell carcinomas, infiltrating ductal breast carcinomas, anaplastic astrocytomas and glioblastomas, colorectal cancer, leukemia, ovarian cancer, prostate cancer, gastric cancer, and many human cancer cell lines . In addition, recently, pharmacological approaches to inhibit FoxM1 expression in animal models of cancers have been reported, suggesting that drugs targeting FoxM1 may open new avenues in cancer therapy. Although there have been several reports regarding FoxM1 expression in HCC tissues using immunohistochemical analyses, these analyses were limited mainly to hepatitis B virus (HBV)‐infected subjects .…”

Section: Introductionmentioning

confidence: 74%

Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma

Egawa

Yoshida

Ogura

et al. 2017

Hepatology Research

View full text Add to dashboard Cite

show abstract

“…We note that FOXM1 has been experimentally confirmed as an important target in high-risk MM. 32 FOXM1 is most significantly activated by E2F1 in the MM TRN (Spearman correlation: p < 1e-172; E2F1 motif in FOXM1 promoter ). All high-risk subtypes, with the exception of t(4;14), were causally upstream of FOXM1 activation via the intermediate up-regulation of E2F1 in the CM TRN.…”

Section: Resultsmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

View full text Add to dashboard Cite

38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

show abstract

FOXM1 is a therapeutic target in high-risk multiple myeloma

Cited by 4 publications

References 46 publications

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Contact Info

Product

Resources

About