Low <i>CREBBP</i> expression is associated with adverse long‐term outcomes in paediatric acute lymphoblastic leukaemia

Gao, Chao; Zhang, Rui‐Dong; Zhao, Xiao-Xi; Cui, Lei; Yue, Zhixia; Li, Weijing; Chen, Zhenping; Li, Zhigang; Rao, Qing; Wang, Min; Zheng, Huyong; Wang, Jianxiang

doi:10.1111/ejh.12897

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…Again, many of these mutations were present in the corresponding diagnostic samples, but CREBBP mutations were absent in diagnostic samples from children who were cured [26] . Consistent with these findings, another more recent study demonstrated that low CREBBP expression at diagnosis is associated with a poor clinical response to glucocorticoids and with increased MRD following the first month of therapy [27] , providing clinical evidence that loss of CREBBP activity may contribute to chemoresistance.…”

Section: Histone Acetylationmentioning

confidence: 53%

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

Meyer¹,

Hermiston²

2019

CDR

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Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The genomic landscape of pediatric ALL has been extensively characterized, allowing for the identification of distinct molecular subtypes of this disease. This in turn has facilitated improvements in risk stratification and tailoring of therapy, resulting in dramatic improvements in survival rates over the past several decades. However, despite these improvements, outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse. Although the genetic landscape of pediatric ALL is wellunderstood, increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse. Instead, cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL, and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse. This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis, progression, and response to therapy, and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL.

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Section: Histone Acetylationmentioning

confidence: 53%

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

Meyer¹,

Hermiston²

2019

CDR

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“…Among the 10 hub DMGs revealed in our analysis, six (STAT3, PTPN6, SYK, STAT5B,and XPO1, and ABL1) had known CLL relevance; hence, our results corroborated previous data. The remaining four (UBC, GRB2, CREBBP, and GAB2) have never been reported in previous CLL studies [38][39][40][41][42][43][44][45][46][47][48] . UBC represents a ubiquitin gene (ubiquitin C) and has been described in cancers infrequently.…”

Section: Discussionmentioning

confidence: 73%

“…GRB2 encodes growth factor receptor-bound protein 2 and has been described in cancers relatively frequently; as such, anti-cancer therapeutics targeting GRB2 are currently in development 48 . CREBBP encodes chromatin-modifying enzymes such as the histone acetyl-transferases and has been studied in diffuse large B cell lymphoma, acute lymphoblastic leukaemia, and lung cancer [41][42][43][44][45] . GAB2 encodes the GRB2 associated binding protein 2 46 and has been studied in breast cancer, ovarian cancer, hepatocellular carcinoma, lung cancer, and melanoma 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study

Kim

Lee

Zang

et al. 2020

Sci Rep

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Chronic lymphocytic leukaemia (CLL) exhibits differences between Asians and Caucasians in terms of incidence rate, age at onset, immunophenotype, and genetic profile. We performed genomewide methylation profiling of CLL in an Asian cohort for the first time. Eight Korean patients without somatic immunoglobulin heavy chain gene hypermutations underwent methyl-cpG-binding domain sequencing (MBD-seq), as did five control subjects. Gene Ontology, pathway analysis, and networkbased prioritization of differentially methylated genes were also performed. More regions were hypomethylated (2,062 windows) than were hypermethylated (777 windows). Promoters contained the highest proportion of differentially methylated regions (0.08%), while distal intergenic and intron regions contained the largest number of differentially methylated regions. Protein-coding genes were the most abundant, followed by long noncoding and short noncoding genes. The most significantly over-represented signalling pathways in the differentially methylated gene list included immune/ cancer-related pathways and B-cell receptor signalling. Among the top 10 hub genes identified via network-based prioritization, four (UBC, GRB2, CREBBP, and GAB2) had no known relevance to cLL, while the other six (STAT3, PTPN6, SYK, STAT5B, XPO1, and ABL1) have previously been linked to cLL in Caucasians. As such, our analysis identified four novel candidate genes of potential significance to Asian patients with CLL. Chronic lymphocytic leukaemia (CLL) is characterized by the co-expression of CD5 and CD23 in monomorphic small B-cells; it is the most common leukaemia among adults in Western countries, especially the elderly 1. CLL among Asians differs from that among Caucasians in terms of the incidence rate, median age at onset, phenotype, and the genetic profile. The incidence rates per 100,000 person-years in Korea and Japan are 0.04 and 0.48, respectively, but the rate is 3.83 in Western countries 2. The median age at initial CLL diagnosis is 61 and 70 years among Asians and Caucasians, respectively 2. A single-institution study in South Korea found that 56% of patients had an atypical immunophenotype with high frequencies of FMC7 positivity and strong CD22 positivity 3. A Chinese study showed that TP53 mutations are more common in Chinese patients with CLL than in Caucasian patients, whereas SF3B1 mutations are less common 4. Furthermore, a Korean study found that the frequencies of mutations in ATM, TP53, KLHL6, BCOR, and CDKN2A tend to be higher in Koreans than in Caucasians, while those in SF3B1, NOTCH1, CHD2, and POT1 tend to be lower 2. DNA methylation directly impacts human genome function, and multiple studies have demonstrated the existence of aberrant epigenetic changes that play important roles in tumour initiation and progression in Western patients with CLL 5-8. Recent advances in high-throughput techniques have enabled genome-wide methylation profiling in Caucasians with CLL. For example, an array study identified methylation in seven known or candidate

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“…Broadly, this includes effects on DNA methylation, histone methylation, and histone acetylation, with differential effects depending on the pathway targeted and proteins involved. Implicated proteins, either due to direct mutation, overexpression, or due to novel interactions with other oncogenes, include KMT2A [170,171] (aka MLL), DOT1L [172] , EZH2 [173][174][175] , KDM1A [176][177][178] (aka LSD1), CREBBP [179,180] , SWI/SNF, SETD2 [181,182] , ATRX [183,184] , and H3F3A [185][186][187] (aka Histone 3.3) mutations, to name a few, as well as the HDAC family [188][189][190][191][192] . Most of these proteins have effects across the genome, so elucidation of specific effects is complex.…”

Section: Epigenetic and Mirna-mediated Resistance In Pediatric Cancersmentioning

confidence: 99%

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Shah¹

2019

CDR

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While advances in the treatment of pediatric cancers have improved survival to > 80% across all tumor types, drug resistance continues to limit survival for a considerable number of patients. We review the known mechanisms of resistance in pediatric cancers, including processes that impair conventional chemotherapies, newer classes of targeted small molecule antineoplastic drugs, and monoclonal antibodies. We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers. We also discuss newer areas of research into drug resistance, including extracellular and immune factors.

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Low CREBBP expression is associated with adverse long‐term outcomes in paediatric acute lymphoblastic leukaemia

Abstract: These findings indicate that low-CREBBP is predictive of unfavourable outcomes; thus, a more intensive treatment protocol is necessitated for standard-risk patients with insufficient CREBBP and that a specific target therapy is necessitated for high-risk patients.

Cited by 14 publications

References 41 publications

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

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