The oncofusion protein FUS–ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

Sotoca, Ana M.; Prange, K.H.M.; Reijnders, B; Mandoli, Amit; Nguyen, Luan N.; Stunnenberg, Henk; Martens, Joost H.A.

doi:10.1038/onc.2015.261

Cited by 42 publications

(55 citation statements)

References 53 publications

(62 reference statements)

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“…This rare FUS-ERG transgene has also been noted in ALL and AML and found to modulate the retinoic acid pathway in AML [38]. In addition, Cironi et.…”

Section: Resultsmentioning

confidence: 97%

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

et al. 2016

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Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

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“…This rare FUS-ERG transgene has also been noted in ALL and AML and found to modulate the retinoic acid pathway in AML [38]. In addition, Cironi et.…”

Section: Resultsmentioning

confidence: 97%

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

et al. 2016

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“…NRAMP1 epigenetic profile in different AML models [139,141,142,143,144] may therefore inform on TF spatiotemporal contribution to regulate NRAMP1 expression.…”

Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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“…We accessed RARα and RNA polymerase II chromatin immunoprecipitation sequencing (ChIP‐seq) data from ATRA‐treated NB4 (GSE18886) and TSU‐1621‐MT (GSE60477) cells in WIG format (the summary output post alignment and MACS peak calling) from the NCBI‐GEO database. We visualized RARα and RNA polymerase II binding within the TFEB and p62/sqstm1 loci using Integrated Genome Viewer software (https://www.broadinstitute.org/igv/home).…”

Section: Methodsmentioning

confidence: 99%

“…We accessed RARα and RNA polymerase II chromatin immunoprecipitation sequencing (ChIP-seq) data from ATRA-treated NB4 (GSE18886) 7 and TSU-1621-MT (GSE60477) 31…”

Section: Chip-sequencing Analysismentioning

confidence: 99%

All‐trans retinoic acid (ATRA)‐induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

Orfali

O’Donovan

Cahill

et al. 2020

European J of Haematology

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Objective In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML‐RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all‐trans‐retinoic acid (ATRA) can restore retinoid‐induced transcription and promote degradation of the PML‐RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re‐modeling. Recent studies have identified autophagy as an integral component of ATRA‐induced myeloid differentiation. Methods As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy‐related transcripts. Results ATRA altered the expression of >80 known autophagy‐related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5‐fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA‐resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA. Conclusions We show for the first time that TFEB plays an important role in ATRA‐induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156).

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The oncofusion protein FUS–ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

Cited by 42 publications

References 53 publications

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

All‐trans retinoic acid (ATRA)‐induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

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