High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML

Jo, Aoi; Mitani, Sachiyo; Shiba, Norio; Hayashi, Yasuhide; Hara, Yusuke; Takahashi, Hiro; Tsukimoto, Ichiro; Tawa, Akio; Horibe, Keizo; Tomizawa, Daisuke; Taga, Takashi; Adachi, Souichi; Yoshida, Takemi; Ichikawa, Hitoshi

doi:10.1038/leu.2015.5

Cited by 47 publications

(52 citation statements)

References 30 publications

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“…PRDM16, also known as MEL1, contains an N-positive regulatory (PR) domain homologous to SET domain, and has been shown to direct cytoplasmic H3K9me1 methylation [42]. Chromosomal translocations involving MEL1 or its overexpression have been found in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [43]. However, whether PRDM16 plays any role in breast cancer or other types of solid tumors is completely unknown.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

et al. 2016

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A B S T R A C TMetabolic reprogramming such as the aerobic glycolysis or Warburg effect is well recognized as a common feature of tumorigenesis. However, molecular mechanisms underlying metabolic alterations for tumor therapeutic resistance are poorly understood. Through gene expression profiling analysis we found that histone H3K36 methyltransferase NSD2/MMSET/WHSC1 expression was highly elevated in tamoxifenresistant breast cancer cell lines and clinical tumors. IHC analysis indicated that NSD2 protein overexpression was associated with the disease recurrence and poor survival. Ectopic expression of NSD2 wild type, but not the methylase-defective mutant, drove endocrine resistance in multiple cell models and xenograft tumors. Mechanistically, NSD2 was recruited to and methylated H3K36me2 at the promoters of key glucose metabolic enzyme genes. Its overexpression coordinately up-regulated hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD), two key enzymes of glycolysis and the pentose phosphate pathway (PPP), as well as TP53-induced glycolysis regulatory phosphatase TIGAR. Consequently, NSD2-driven tamoxifen-resistant cells and tumors displayed heightened PPP activity, elevated NADPH production, and reduced ROS level, without significantly altered glycolysis. These results illustrate a coordinated, epigenetic activation of key glucose metabolic enzymes in therapeutic resistance and nominate methyltransferase NSD2 as a potential therapeutic target for endocrine resistant breast cancer.© 2016 Elsevier Ireland Ltd. All rights reserved. IntroductionTumor growth involves reprogrammed glucose metabolism, featured in aerobic glycolysis, to meet the high demand of glycolytic intermediates for biosynthesis of macromolecules. The pentose phosphate pathway (PPP) is a major cellular source of NADPH, in addition to its supply of precursors for nucleotide biosynthesis. Deregulated PPP has been suggested to promote cancer progression and therapy resistance [1]. The activities of PPP can be decreased by p53, as well as being hyperactivated by oncogenic signaling [2][3][4][5]. Functioning as a fructose-2,6-bisphosphatase (F2,6bPase), TIGAR (TP53-induced glycolysis and apoptosis regulator) can enhance glucose carbon flux to the PPP by dampening glycolysis and is required for the development of intestinal adenomas [6][7][8][9]. As a glycolysis modulator, TIGAR was shown to localize in cytoplasm and associate with mitochondria in complex with the hexokinase HK2 in response to hypoxia [7]. HK2, one of the hexokinases that catalyze the first and rate-limiting step of glucose metabolism, is highly expressed in most tumor cells. HK2 plays a pivotal role in diversion of glucose into pathways such as the PPP for enhanced anabolic metabolism required for tumor growth [10,11]. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the PPP and plays a key role in production of NADPH, the major cellular source of reducing power. However, the mechanism of how the different metabolic genes are coordinately regulat...

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Section: Discussionmentioning

confidence: 99%

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

et al. 2016

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“…However, EVI1 did not appear as an independent marker in childhood AML in a multivariate model including favourable karyotype, WBC and age (Balgobind et al, 2010a). Recently, Jo et al (2015) suggested that concomitantly high expression of EVI1 and PRDM16 (also termed MEL1), an EVI1 family member, might act as an even superior prognostic marker in paediatric AML as compared to EVI1 overexpression alone.…”

Section: Evi1 Overexpression and Prognosismentioning

confidence: 99%

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Hinai¹,

Valk²

2016

Br J Haematol

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Deregulated expression of the ecotropic virus integration site 1 (EVI1) gene is the molecular hallmark of therapy-resistant myeloid malignancies bearing chromosomal inv(3)(q21q26·2) or t(3;3)(q21;q26·2) [hereafter referred to as inv(3)/t(3;3)] abnormalities. EVI1 is a haematopoietic stemness and transcription factor with chromatin remodelling activity. Interestingly, the EVI1 gene also shows overexpression in 6-11% of adult acute myeloid leukaemia (AML) cases that do not carry any 3q aberrations. Deregulated expression of EVI1 is strongly associated with monosomy 7 and 11q23 abnormalities, which are known to be associated with poor response to treatment. However, EVI1 overexpression has been revealed as an important independent adverse prognostic marker in adult AML and defines distinct risk categories in 11q23-rearranged AML. Recently, important progress has been made in the delineation of the mechanism by which EVI1 becomes deregulated in inv(3)/t(3;3) as well as the cooperating mutations in this specific subset of AML with dismal prognosis.

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“…Several factors affecting AML prognosis have been identified, including somatic mutations in genes such as NPM1, FLT3-ITD, CEBPA, WT1, ASXL1, IDH1/2, DNMT3A , and RUNX1 [6–10]. Moreover, expression levels of LFE1 [11], CXXC5 [12], EVL1, MEL1 [13], and miR-9* [14] are also reported to be associated with AML prognosis. However, only a small part of AML prognosis variation can be explained by these above-mentioned factors.…”

Section: Introductionmentioning

confidence: 99%

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

et al. 2016

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The prognosis of cytogenetically normal acute myeloid leukemia (CN-AML) varies greatly among patients. Achievement of complete remission (CR) after chemotherapy is indispensable for a better prognosis. To develop a gene signature predicting overall survival (OS) in CN-AML, we performed data mining procedure based on whole genome expression data of both blood cancer cell lines and AML patients from open access database. A gene expression signature including 42 probes was derived. These probes were significantly associated with both cytarabine half maximal inhibitory concentration values in blood cancer cell lines and OS in CN-AML patients. By using cox regression analysis and linear regression analysis, a chemo-sensitive score calculated algorithm based on mRNA expression levels of the 42 probes was established. The scores were associated with OS in both the training sample (p=5.13 × 10−4, HR=2.040, 95% CI: 1.364-3.051) and the validation sample (p=0.002, HR=2.528, 95% CI: 1.393-4.591) of the GSE12417 dataset from Gene Expression Omnibus. In The Cancer Genome Atlas (TCGA) CN-AML patients, higher scores were found to be associated with both worse OS (p=0.013, HR=2.442, 95% CI: 1.205-4.950) and DFS (p=0.015, HR=2.376, 95% CI: 1.181-4.779). Results of gene ontology (GO) analysis showed that all the significant GO Terms were correlated with cellular component of mitochondrion. In summary, a novel gene set that could predict prognosis of CN-AML was identified presently, which provided a new way to identify genes impacting AML chemo-sensitivity and prognosis.

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High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML

Cited by 47 publications

References 30 publications

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

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