Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

Tamai, Minori; Kasai, Shin; Akahane, Koshi; Nguyen, Thao; Kagami, Keiko; Komatsu, Chiaki; Abe, Masako; Watanabe, Atsushi; Goi, Kumiko; Miyake, Kunio; Inaba, Toshiya; Takita, Junko; Goto, Hiroaki; Minegishi, Masayoshi; Iwamoto, Shotaro; Sugita, Kanji; Inukai, Takeshi

doi:10.1016/j.jsbmb.2022.106068

Cited by 7 publications

(10 citation statements)

References 53 publications

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“…Despite the many functional studies that use REH, few have addressed the genomic aberrations underlying its phenotype. The BTG1 deletion identified in the present study has been previously noted in analyses of REH using arrays 55 and PCR 46 , while NR3C1 has an established nonsense (p.Gln528Ter) mutation on one allele 56 and a deletion on the other 57 . Recurrent deletions of TBL1XR1 , which encodes for nuclear hormone receptor co-repressors, have been shown to contribute to dysregulated gene expression and GC resistance in ETV6-RUNX1 positive ALL, including REH 58,59 .…”

Section: Discussionsupporting

confidence: 72%

A complete digital karyotype of the B-cell leukemia REH cell line resolved by long-read sequencing

Wiklander

Arvidsson

Bunikis

et al. 2023

Preprint

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The B-cell acute lymphoblastic leukemia (ALL) cell line REH, with the t(12;21) ETV6-RUNX1 translocation, is known to have a complex karyotype defined by a series of large-scale chromosomal rearrangements. Taken from a 15-year-old at relapse, the cell line offers a practical model for the study of high-risk pediatric B-ALL patients. In recent years, short-read DNA and RNA sequencing have emerged as a complement to analog karyotyping techniques in the resolution of structural variants in an oncological context. However, it is challenging to create a comprehensive digital karyotype of a genome with these techniques alone. Here, we explore the integration of long-read PacBio and Oxford Nanopore whole genome sequencing (WGS), IsoSeq RNA-sequencing, and short-read sequencing to create a detailed digital karyotype of the REH cell line. WGS refined the breakpoints of known aberrations and clarified the molecular traits of disrupted ALL-associated genes BTG1 and TBL1XR1, as well as the glucocorticoid receptor NR3C1. Several previously underreported structural variants were also uncovered, including deletions affecting the ALL-associated genes VPREB1 and NFATC1. Meanwhile, transcriptome sequencing identified seven fusion genes within the genomic breakpoints. Together, our extensive whole-genome investigation makes high-quality open-source data available to the leukemia genomics community.

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Section: Discussionsupporting

confidence: 72%

A complete digital karyotype of the B-cell leukemia REH cell line resolved by long-read sequencing

Wiklander

Arvidsson

Bunikis

et al. 2023

Preprint

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“…However, Tamai et al failed to find an association between the mutational status of the CREBBP gene and dexamethasone sensitivity in pre-B ALL. They suggested that most T-ALL cell lines were resistant to dexamethasone regardless of the mutational status of CREBBP [148]. Regardless of CREBBP mutation states and chromosomal aberrations, ICG-001 eradicated chemoresistance in vitro and significantly prolonged the survival of NOD/SCID mice engrafted with primary ALL [149].…”

Section: Crebbp/ep300 and Chemoresistance In Hematological Malignanciesmentioning

confidence: 99%

The Role of CREBBP/EP300 and Its Therapeutic Implications in Hematological Malignancies

Zhu

Wang

et al. 2023

Cancers

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Disordered histone acetylation has emerged as a key mechanism in promoting hematological malignancies. CREB-binding protein (CREBBP) and E1A-binding protein P300 (EP300) are two key acetyltransferases and transcriptional cofactors that regulate gene expression by regulating the acetylation levels of histone proteins and non-histone proteins. CREBBP/EP300 dysregulation and CREBBP/EP300-containing complexes are critical for the initiation, progression, and chemoresistance of hematological malignancies. CREBBP/EP300 also participate in tumor immune responses by regulating the differentiation and function of multiple immune cells. Currently, CREBBP/EP300 are attractive targets for drug development and are increasingly used as favorable tools in preclinical studies of hematological malignancies. In this review, we summarize the role of CREBBP/EP300 in normal hematopoiesis and highlight the pathogenic mechanisms of CREBBP/EP300 in hematological malignancies. Moreover, the research basis and potential future therapeutic implications of related inhibitors were also discussed from several aspects. This review represents an in-depth insight into the physiological and pathological significance of CREBBP/EP300 in hematology.

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“…Cells used in this study are listed in Online Supplementary Tables S1 and S2. YCUB5 (30) and KOPN49 (22,31) were provided by Hiroaki Goto (Kanagawa Children's Medical Center) and Takeshi Inukai (University of Yamanashi), respectively. Cell authentication was made using the GenePrint 10 System (Promega) with Expasy Cellosaurus short tandem repeat (STR) reference, except for YCUB5 and KOPN49, which lacked such reference.…”

Section: Cellsmentioning

confidence: 99%

BCL6 inhibition ameliorates resistance to ruxolitinib in <i>CRLF2</i>-rearranged acute lymphoblastic leukemia

et al. 2022

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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is intractable and mostly harbors genetic alterations that activate JAK or ABL signaling. The commonest subtype of Ph-like ALL exhibits the CRLF2 gene arrangement that brings about JAK1/2-STAT5 pathway activation. However, JAK1/2 inhibition alone is insufficient for treatment, necessitating combinatorial therapies targeting multiple signals. To better understand the mechanisms underlying the insufficient efficacy of JAK inhibition, this study explored gene expression changes upon treatment with a JAK1/2 inhibitor (ruxolitinib) and revealed BCL6 elevation as one such mechanism. Upregulated BCL6 suppressed TP53 expression along with its downstream cell cycle inhibitor p21 (CDKN2A) and proapoptotic molecules, such as FAS, TNFRSF10B, BID, BAX, BAK, PUMA, and NOXA, conferring cells in part with therapy resistance. The BCL6 inhibition (FX1) alone was able to upregulate TP53 and restore TP53 expression that ruxolitinib had diminished. In addition, ruxolitinib and FX1 concertedly downregulated MYC. As a result, FX1 treatment alone had growth-inhibitory and apoptosis-sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged xenografted mice survival. These findings provide one mechanism for the insufficiency of JAK inhibition for CRLF2-rearranged ALL treatment and BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.

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Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

Cited by 7 publications

References 53 publications

A complete digital karyotype of the B-cell leukemia REH cell line resolved by long-read sequencing

A complete digital karyotype of the B-cell leukemia REH cell line resolved by long-read sequencing

The Role of CREBBP/EP300 and Its Therapeutic Implications in Hematological Malignancies

BCL6 inhibition ameliorates resistance to ruxolitinib in <i>CRLF2</i>-rearranged acute lymphoblastic leukemia

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