RUNX1T1

Gene Summary

Gene:RUNX1T1; RUNX1 partner transcriptional co-repressor 1
Aliases: CDR, ETO, MTG8, AML1T1, ZMYND2, CBFA2T1, AML1-MTG8
Location:8q21.3
Summary:This gene encodes a member of the myeloid translocation gene family which interact with DNA-bound transcription factors and recruit a range of corepressors to facilitate transcriptional repression. The t(8;21)(q22;q22) translocation is one of the most frequent karyotypic abnormalities in acute myeloid leukemia. The translocation produces a chimeric gene made up of the 5'-region of the runt-related transcription factor 1 gene fused to the 3'-region of this gene. The chimeric protein is thought to associate with the nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein CBFA2T1
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplasm Proteins
  • Karyotyping
  • Recombinant Fusion Proteins
  • Acute Myeloid Leukaemia
  • Gene Expression Profiling
  • Proto-Oncogene Proteins
  • Chromosome 8
  • Cell Differentiation
  • Cancer Gene Expression Regulation
  • RTPCR
  • Bone Marrow
  • Biomarkers, Tumor
  • Transcription
  • Zinc Fingers
  • Leukemic Gene Expression Regulation
  • DNA-Binding Proteins
  • Leukaemia
  • Residual Disease
  • Promoter Regions
  • Amino Acid Sequence
  • Repressor Proteins
  • Childhood Cancer
  • RUNX1 Translocation Partner 1 Protein
  • Core Binding Factor Alpha 2 Subunit
  • Messenger RNA
  • Polymerase Chain Reaction
  • RUNX1
  • Oncogene Fusion Proteins
  • Translocation
  • Transcription Factors
  • Adolescents
  • Hematopoietic Stem Cells
  • FISH
  • Neoplastic Cell Transformation
  • Chromosome 21
  • Recurrence
  • Base Sequence
  • Mutation
  • Molecular Sequence Data
  • Myeloid Leukemia
  • Cell Line
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
LeukaemiaRUNX1T1 and Myeloid Leukemia View Publications233
Acute Myeloid Leukaemia (AML)RUNX1T1 and Acute Myeloid Leukaemia View Publications191
-RUNX1T1 and Residual Disease View Publications29
Acute Myeloid Leukaemia (AML) t(8;21)(q22;q22) in Acute Myeloid Leukemia
The t(8;21) translocation is the most frequent cytogenetic abnormality in acute myeloid leukaemia (AML). The translocation fuses the RUNX1 (CBFA2, AML1) gene on chromosome 21q to the RUNX1T1 (CBFA2T1, ETO) gene on chromosome 8q. The resulting fusion gene AML1-ETO occurs more frequently, though not exclusively, in the AML-M2 sub-type. In a series of 64 AML cases Andrieu et al (1996) detected the fusion in 3% (1/32) of M1 patients compared to 8/32 (25%) with M2. It is detected in approximately 20% of adult and 40% of paediatric patients with AML-M2.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RUNX1T1 (cancer-related)

Nishizawa Y, Ikeda R, Yamamoto M, et al.
5-Aza-2-deoxycytidine Enhances the Sensitivity of 5-Fluorouracil by Demethylation of the Thymidine Phosphorylase Promoter.
Anticancer Res. 2019; 39(8):4129-4136 [PubMed] Related Publications
BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP).
MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively.
RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU.
CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.

Wang X, Lyu J, Ji A, et al.
Jarid2 enhances the progression of bladder cancer through regulating PTEN/AKT signaling.
Life Sci. 2019; 230:162-168 [PubMed] Related Publications
AIMS: Jumonji AT-rich interactive domain 2 (Jarid2) is an interacting component of PRC2 which catalyzes methylation of H3K27 (H3K27me3) and causes the downregulation of PTEN. In the present study, we aimed to explore whether Jarid2 could interact with H3K27me3 to regulate PTEN expression in bladder cancer.
MAIN METHODS: Jarid2 expression in bladder cancer tissues and cells were determined by western blotting and RT-PCR. CCK-8, flow cytometry, transwell chamber and in vivo xenograft assays were performed to assess cell growth, apoptosis, migration and tumorigenesis, respectively. Chromatin immunoprecipitation (ChIP) assay was used to assess the methylation of PTEN.
KEY FINDINGS: Jarid2 expression was increased in bladder cancer tissues and cells. Downregulation of Jarid2 with shRNA transfection obviously inhibited the proliferation, migration and tumorigenesis of bladder cancer T24 and HT-1376 cells and induced cell apoptosis. Jarid2 downregulation decreased the expression of p-AKT and increased PTEN expression. Besides, Jarid2 down-regulation repressed the epithelial-mesenchymal transition (EMT), whereas knockdown of PTEN impaired this effect. Moreover, upregulation of Jarid2 increased the combination of PTEN promoter and H3K27me3, and 5-aza-CdR rescued it. Meanwhile, 5-aza-CdR administration abolished Jarid2 roles in the promotion of EMT process and AKT activation, as well as the reduction of PTEN expression.
SIGNIFICANCE: Overall, the present study elaborated that Jarid2 facilitated the progression of bladder cancer through H3K27me3-mediated PTEN downregulation and AKT activation, which might provide a new mechanism for Jarid2 in promoting bladder cancer progression.

Kiyozumi Y, Baba Y, Okadome K, et al.
Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer.
Cancer Sci. 2019; 110(6):1863-1871 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune-based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5-azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin-fixed, paraffin-embedded samples resected from esophageal cancer patients. We treated cell lines with 5-azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = -0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.

Kurahashi R, Kadomatsu T, Baba M, et al.
MicroRNA-204-5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma.
Cancer Sci. 2019; 110(6):1897-1908 [PubMed] Free Access to Full Article Related Publications
Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early-stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC-TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)-204-5p levels in urinary exosomes of 40-week-old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA-204-5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR-204-5p-containing exosomes. Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR-204-5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC-TFE3 fusion gene. These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.

Yun JW, Bae YK, Cho SY, et al.
Elucidation of Novel Therapeutic Targets for Acute Myeloid Leukemias with
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
The

Shin HJ, Min WS, Min YH, et al.
Different prognostic effects of core-binding factor positive AML with Korean AML registry data.
Ann Hematol. 2019; 98(5):1135-1147 [PubMed] Related Publications
Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.

van der Kouwe E, Staber PB
RUNX1-ETO: Attacking the Epigenome for Genomic Instable Leukemia.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Oncogenic fusion protein RUNX1-ETO is the product of the t(8;21) translocation, responsible for the most common cytogenetic subtype of acute myeloid leukemia. RUNX1, a critical transcription factor in hematopoietic development, is fused with almost the entire ETO sequence with the ability to recruit a wide range of repressors. Past efforts in providing a comprehensive picture of the genome-wide localization and the target genes of RUNX1-ETO have been inconclusive in understanding the underlying mechanism by which it deregulates native RUNX1. In this review; we dissect the current data on the epigenetic impact of RUNX1 and RUNX1-ETO. Both share similarities however, in recent years, research focused on epigenetic factors to explain their differences. RUNX1-ETO impairs DNA repair mechanisms which compromises genomic stability and favors a mutator phenotype. Among an increasing pool of mutated factors, regulators of DNA methylation are frequently found in t(8;21) AML. Together with the alteration of both, histone markers and distal enhancer regulation, RUNX1-ETO might specifically disrupt normal chromatin structure. Epigenetic studies on the fusion protein uncovered new mechanisms contributing to leukemogenesis and hopefully will translate into clinical applications.

Liu N, Song J, Xie Y, et al.
Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis.
Proc Natl Acad Sci U S A. 2019; 116(3):890-899 [PubMed] Free Access to Full Article Related Publications
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene,

Bashanfer SAA, Saleem M, Heidenreich O, et al.
Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1‑RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells.
Oncol Rep. 2019; 41(3):2027-2040 [PubMed] Related Publications
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.

Yu M, Xu Y, Pan L, et al.
miR-10b Downregulated by DNA Methylation Acts as a Tumor Suppressor in HPV-Positive Cervical Cancer via Targeting Tiam1.
Cell Physiol Biochem. 2018; 51(4):1763-1777 [PubMed] Related Publications
BACKGROUND/AIMS: microRNAs (miRNAs) are known to act as oncogenes or tumor suppressors in diverse cancers. Although miR-10b is an oncogene implicated in many tumors, its role in cervical cancer (CC) remains largely unclear. Here, we investigated the function and underlying mechanisms of miR-10b in human CC.
METHODS: Quantitative RT-PCR was used to measure miR-10b expression in CC and normal tissues, and its association with clinicopathologic features was analyzed. Methylation of CpG sites in the miR-10b promoter was analyzed by methylation sequencing. Cell proliferation, apoptosis, migration, and invasion assays were used to elucidate the biological effects of miR-10b and expression of the target gene was assayed with Western blot.
RESULTS: miR-10b was downregulated in CC tissues compared with normal tissues, and less miR-10b expression was associated with larger tumors, vascular invasion and HPV-type 16 positivity. miR-10b expression decreased in HeLa (HPV18-positive) and SiHa (HPV16-positive) cells compared with C-33A (HPV-negative), but increased after treatment with 5-Aza-CdR. Methylation ratio of site -797 in the miR-10b promoter in C-33A was lower than that in HeLa and SiHa. Further analysis indicates that site -797 is located within a transcription factor AP-2A (TFAP2A) binding element. Functionally, overexpression of miR-10b in HeLa and SiHa suppressed cell proliferation, migration and invasion, and induced apoptosis and miR-10b downregulation had opposite effects. Mechanistically, T-cell lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct and functional target of miR-10b.
CONCLUSION: miR-10b acts as a tumor suppressor in CC by suppressing oncogenic Tiam1, and its expression may be downregulated through methylation of TFAP2A binding element by HPV.

Shi J, Zhong X, Song Y, et al.
Long non-coding RNA RUNX1-IT1 plays a tumour-suppressive role in colorectal cancer by inhibiting cell proliferation and migration.
Cell Biochem Funct. 2019; 37(1):11-20 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the progression of various cancers. In this study, we aim to investigate the role of lncRNA RUNX1-IT1 in the development of colorectal cancer (CRC). The expression levels of lncRNA RUNX1-IT1 were measured using quantitative real-time Polymerase Chain Reaction(qRT-PCR). CCK8 proliferation assay, transwell assay, and flow cytometry were performed to evaluate the effect of lncRNA RUNX1-IT1 on CRC cell proliferation, migration, and apoptosis. The proliferation markers (PCNA, Ki67), apoptosis markers (cleaved-PARP, cleaved-caspase3), and MMP9 are detected by western blotting. Significant down regulation of lncRNA RUNX1-IT1 was measured in CRC tissues and three CRC cell lines (HCT116, HT29, and RKO) compared with paired nontumorous adjacent tissues (P < 0.01) or the normal colonic epithelial cell line FHC (P < 0.05), respectively. Moreover, the proliferative and migration potential of CRC cells were inhibited by overexpressing lncRNA RUNX1-IT1, which could be obviously improved by knocking down lncRNA RUNX1-IT1. The protein levels of PCNA, Ki67, and MMP9 were upregulated by overexpressing lncRNA RUNX1-IT1 and down regulated in si-RUNX1-IT1 cells. Besides, lncRNA RUNX1-IT1 could also promote the apoptosis of CRC cells. In conclusion, lncRNA RUNX1-IT1 is downregulated in CRC and plays a tumour-suppressive role due to the regulatory of cell proliferation, migration, and apoptosis. SIGNIFICANCE OF THE STUDY: We demonstrated that lncRNA RUNX1-IT1 was down regulated both in CRC tissues and cell lines. Besides, lncRNA RUNX1-IT1 could serve as a potential diagnostic biomarker and play a tumour-suppressive role owing to its good diagnostic efficacy and inhibition of CRC cell proliferation and migration.

Naarmann-de Vries IS, Sackmann Y, Klein F, et al.
Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region.
Leuk Res. 2019; 76:15-23 [PubMed] Related Publications
Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q).

Platzbecker U, Middeke JM, Sockel K, et al.
Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.
Lancet Oncol. 2018; 19(12):1668-1679 [PubMed] Related Publications
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.
METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m
FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis p
INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.
FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.

Masuishi T, Taniguchi H, Eto T, et al.
Morphologic Response and Tumor Shrinkage as Early Predictive Markers in Unresectable Colorectal Liver Metastases.
Anticancer Res. 2018; 38(11):6501-6506 [PubMed] Related Publications
BACKGROUND/AIM: Anti-EGFR antibodies or bevacizumab comprise first-line treatment for patients with RAS wild-type colorectal liver metastases (CLM). Which marker better predicts efficacy, early tumor shrinkage or morphologic response, still remains unclear.
PATIENTS AND METHODS: We retrospectively evaluated 155 patients with KRAS exon 2 wild-type CLM treated with bevacizumab (BEV group) or anti-EGFR antibodies (EGFR group). Three radiologists independently assessed early tumor shrinkage (ETS) and early optimal morphologic response (EOMR) from baseline and first follow-up CT scan.
RESULTS: Patients with ETS had longer progression-free survival (PFS) than those without ETS [hazard ratio (HR)=0.69] and ETS tended to be observed in the EGFR group, while patients with EOMR had longer PFS than those without EOMR (HR=0.64) and EOMR tended to be observed in the BEV group.
CONCLUSION: Among patients with KRAS exon 2 wild-type CLM, EOMR and ETS may predict better PFS, especially in patients treated with bevacizumab and anti-EGFR antibodies, respectively.

Wu Y, Xu J, Shen K, et al.
Acute myeloid leukemia with new complex t(8;21;22) induced hemophagocytic lymphohistiocytosis: A case report.
Medicine (Baltimore). 2018; 97(44):e12762 [PubMed] Free Access to Full Article Related Publications
RATIONALE: The balanced translocation t(8;21;22)(q22;q22;q11.2) is not reported previously, although t(8;21)(q22;q22) is seen in approximately 7% of adults and most frequent abnormality in children with newly diagnosed acute myeloid leukemia (AML). AML-associated hemophagocytic lymphohistiocytosis (HLH) is a rare event, reported only of limited numbers. The present study reports a very rare case of t(8;21;22)(q22;q22;q11.2) with AML, not reported previously, and developed HLH at the same time.
PATIENT CONCERNS AND DIAGNOSIS: A 15-year-old girl presented with a history of bleeding gums and high fever, leukocytosis, anemia, and thrombocytopenia. While waiting the result of bone marrow aspirate, the HLH-associated examinations were abnormal. Bone marrow aspirate showed a hypercellular marrow with 1% myeloblasts. The cytogenetic and molecular studies revealed the presence of abnormal karyotype-46, XX, t(8;21;22)(q22;q22;q11.2) and RUNX1-RUNX1T1 fusion gene. Genetic detections of HLH showed heterozygous genetic variants in lysosomal trafficking regulator (LYST). Hence, she was diagnosed with AML with t(8;21;22)(q22;q22;q11.2) and HLH.
INTERVENTIONS AND OUTCOMES: All HLH clinical symptoms disappeared after the 4 weeks treatment of HLH. Then the patient received standard AML induction chemotherapy and the leukemia relapsed after 2 cycles of high-dosed consolidation therapy. Eventually, the patient received emergent paternal haploidentical hematopoietic stem cell transplantation based on the complex variant translocation, leukemia replased state and HLH with compound heterozygotes mutation, and achieved sustained remission with RUNX1-RUNX1T1 negative for more than 1 year.
LESSONS: Patients with some specific recurrent cytogenetic abnormalities should be diagnosed with AML regardless of the blast count, for example t(8;21). We should improve the understanding of complex variant translocations. HLH-related genetic mutations were not only found in primary HLH, but also in second HLH.

Martinez-Soria N, McKenzie L, Draper J, et al.
The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.
Cancer Cell. 2018; 34(4):626-642.e8 [PubMed] Free Access to Full Article Related Publications
Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

Wang P, Chu W, Zhang X, et al.
Kindlin-2 interacts with and stabilizes DNMT1 to promote breast cancer development.
Int J Biochem Cell Biol. 2018; 105:41-51 [PubMed] Related Publications
Integrin-interacting protein Kindlin-2, as a focal adhesion protein, promotes growth and progression of breast cancer. However, the precise mechanism that underlie the role of Kindlin-2 in breast cancer is elusive. Here, we report that the expression of Kindlin-2 positively correlated with DNA methyltransferase 1(DNMT1) in breast cancer patients. Further, we found that DNMT1 was upregulated in mammary gland tissues of mammary specific Kindlin-2 transgenic mice. More importantly, high expression of DNMT1 was observed in mammary tumors formed by Kindlin-2 transgenic mice. On the basis of these observations, DNMT inhibitor 5-aza-CdR was used and found its treatment strongly decreased Kindlin-2-induced breast cancer cell proliferation and migration. Mechanistically, Kindlin-2 increased the stability of DNA methyltransferase DNMT1 through interaction with DNMT1 and methylated CpG islands in the E-cadherin promoter. Kindlin-2 increased the occupancy of DNMT1 at E-cadherin promoter, thereby suppressing E-cadherin expression. Taken together, our data reveal that Kindlin-2 promotes breast cancer development by enhancing the stability of DNMT1.

Tsuchiya K, Tabe Y, Ai T, et al.
Eprobe mediated RT-qPCR for the detection of leukemia-associated fusion genes.
PLoS One. 2018; 13(10):e0202429 [PubMed] Free Access to Full Article Related Publications
The detection and quantification of leukemia-associated fusion gene transcripts play important roles in the diagnosis and follow-up of leukemias. To establish a standardized method without interlaboratory discrepancies, we developed a novel one-step reverse transcription quantitative PCR (RT-qPCR) assay, called "the Eprobe leukemia assay," for major and minor BCR-ABL1, RUNX1-RUNX1T1, and various isoforms of PML-RARA. This assay is comprised of Eprobes that are exciton-controlled hybridization-sensitive fluorescent oligonucleotides. Melting curve analyses were performed on synthetic quantitative standard RNAs with strict quality control. Quantification capacity was evaluated by comparison with TaqMan RT-qPCR using 67 primary leukemia patient samples. The lower limit of detection and the limit of quantification of this assay were less than 31.3 copies/reaction and 62.5 copies/reaction, respectively. This assay correctly detected the fusion genes in samples with 100% sensitivity and specificity. The specificity of the reactions was confirmed by melting curve analyses. The assay detected low-level expression of minor BCR-ABL1 co-expressed with major BCR-ABL1. These results illustrate the feasibility and high accuracy of the Eprobe leukemia assay, even for minimal residual disease monitoring.

Kawashima N, Akashi A, Nagata Y, et al.
Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study.
Ann Hematol. 2019; 98(1):83-91 [PubMed] Related Publications
We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.

Sunakawa Y, Yang D, Cao S, et al.
Immune-related Genes to Dominate Neutrophil-lymphocyte Ratio (NLR) Associated With Survival of Cetuximab Treatment in Metastatic Colorectal Cancer.
Clin Colorectal Cancer. 2018; 17(4):e741-e749 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear.
PATIENTS AND METHODS: In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes.
RESULTS: NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = -0.24; P = .040 and r = -0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value < .005; false discovery rate P-value < .15).
CONCLUSION: NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.

Khazayel S, Mokarram P, Mohammadi Z, et al.
Derivative of Stevioside; CPUK02; Restores ESR1 Gene Methylation in MDA-MB 231
Asian Pac J Cancer Prev. 2018; 19(8):2117-2123 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Background: CPUK02 (15-Oxosteviol benzyl ester) is a new ent-kaurenoid derivative of stevioside and exhibits strong anti-cancer activity. Nowadays, the pattern of epigenetic in cancer has been topic of many studies and DNA methylation targeting represents a relevant strategy for cancer treatment. Since, no study conducted to this mechanism, we attempt to evaluate whether CPUK02 induce its anti-cancer effects via alteration the level of mRNA DNMT3B, DNMT3A expression and ESR1 methylation pattern in breast cancer cells line. Methods: MCF-7 (ER +) and MDA-MB231 (ER-) cell lines were treated for 24, 48 hours with 1 μM CPUK02 and 5-AZA-CdR (DNA methyltransferase inhibitor). Quantitative expression of DNMT3B and DNMT3A genes and ESR1 promoter methylation was assessed by Real-Time PCR and MS-PCR, respectively. Results: CPUK02 restored ESR1 promoter unmethylated allele in MDA-MB 231 cells. Also treatment with CPUK02 decreased the expression of both DNMT3A and DNMT3B genes like 5-AZA. The expression of DNMT genes were diminished by half compared with control cells. Conclusions: These results showed that CPUK02 has an anticancer effect on MDA-MB 231 cells which this effect can be done through several pathways.

Liu H, Yan Z, Yin Q, et al.
RUNX3 Epigenetic Inactivation Is Associated With Estrogen Receptor Positive Breast Cancer.
J Histochem Cytochem. 2018; 66(10):709-721 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The role of Runt-related transcription factor 3 ( RUNX3) gene in breast cancer remains not fully understood. We studied the correlation between RUNX3 gene promoter methylation and estrogen receptor (ER) expression status in breast cancer. Three breast cancer cell lines and 113 formalin-fixed, paraffin-embedded breast cancer tissue samples were analyzed for RUNX3 expression. Methylation-specific polymerase chain reaction was used to analyze RUNX3 methylation on the samples. Migration and invasion ability were evaluated in MCF7 cell line (RUNX3 methylated) treated with methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) to study the effect of RUNX3 methylation status. Our data showed that the expression of RUNX3 was high in MCF10A but not in MCF7 and SKBR3 cell lines, while the RUNX3 promoter showed hypermethylation in MCF7 but not in MCF10A and SKBR3. In tissues samples, Immunohistochemical (IHC) expression of RUNX3 protein was higher in ER-negative samples than in ER-positive cases, and it was negatively correlated with the methylation status of the RUNX3 gene promoter. Proliferation, migration, and invasion of MCF7 were suppressed when 5-Aza-CdR treated. Also, the hypermethylation status of RUNX3 gene promoter was reversed and RUNX3 expression was increased. In summary, our data suggest that hypermethylation of the RUNX3 gene promoter may play an important role in ER-positive breast tumor progression.

Jin P, Song Y, Yu G
The Role of Abnormal Methylation of Wnt5a Gene Promoter Regions in Human Epithelial Ovarian Cancer: A Clinical and Experimental Study.
Anal Cell Pathol (Amst). 2018; 2018:6567081 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Objective: In the current study, the role of abnormal methylation of Wnt5a gene promoter regions in human epithelial ovarian cancer was investigated.
Methods: Wnt5a expressions were examined by immunohistochemistry in epithelial ovarian tissues (30 normal and 79 human EOC tissues). SKOV3 cells were treated with different concentrations of 5-Aza-CdR (0.5, 5, and 50 
Results: (1) Compared with normal tissues, Wnt5a expressions were reduced or lost in EOC (
Conclusions: Wnt5a gene region promoter aberrant methylation existed in epithelial ovarian cancer, and abnormal methylation of Wnt5a gene promoter regions may be a new target for the treatment of epithelial ovarian cancer.

Kang X, Feng Y, Gan Z, et al.
NASP antagonize chromatin accessibility through maintaining histone H3K9me1 in hepatocellular carcinoma.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(10):3438-3448 [PubMed] Related Publications
The regulation of histone deposits mediated by multi-chaperone complexes under physiological conditions remains to be further investigated. Here, we studied the function of nuclear autoantigenic sperm protein (NASP) in the regulation of liver cancer. We found that NASP levels in liver tumors were generally higher than in normal liver tissues and NASP down-regulation inhibited liver cancer cells from forming tumors. We further analyzed cellular responses and epigenetic mechanisms of the histone H3-H4 shortage induced by NASP knockdown in liver cancer cells. The results showed that the major effects of NASP knockdown were globally enhanced chromatin accessibility, which facilitates transcription release, and failure of replication initiation. Furthermore, we demonstrated that NASP depletion led to a global decrease of histone H3K9me1 modification associated with newly H3 processing, which occurred directly at the promoters of up-regulated anti-tumor genes BACH2 and RunX1T1. This also resulted in a synergistic effect on enhanced apoptosis with Myc and p53 decreases. Overall, our work provides new insights into the roles of NASP in tumorigenesis and cancer prevention.

Shiota M, Dejima T, Yamamoto Y, et al.
Collateral resistance to taxanes in enzalutamide-resistant prostate cancer through aberrant androgen receptor and its variants.
Cancer Sci. 2018; 109(10):3224-3234 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.

Asada S, Goyama S, Inoue D, et al.
Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.
Nat Commun. 2018; 9(1):2733 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

Vialatte de Pémille C, Berzero G, Small M, et al.
Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies.
Br J Cancer. 2018; 119(1):105-113 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Paraneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger.
METHODS: The transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis.
RESULTS: A prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures.
CONCLUSIONS: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.

Greenblatt SM, Man N, Hamard PJ, et al.
CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis.
Cancer Cell. 2018; 33(6):1111-1127.e5 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML.

Wang N, Che Y, Yin F, et al.
Study on the methylation status of SPINT2 gene and its expression in cervical carcinoma.
Cancer Biomark. 2018; 22(3):435-442 [PubMed] Related Publications
BACKGROUND: Cervical cancer is one of the malignant tumors which seriously threaten the women health worldwide. SPINT2 is an endogenous inhibitor of hepatocyte growth factor activator and down regulated or even silenced in many human malignant tumors.
OBJECTIVE: This study was performed to explore the promoter methylation status of SPINT2 gene and the effect on its expression in cervical carcinoma.
METHODS: HPV-positive and -negative cervical cancer cell lines, 50 cases of cervical carcinoma tissues, and 20 cases of normal cervical tissues were used for this study. The methylation status of promoter and the first exon of SPINT2 gene were analyzed. The expression of SPINT2 was analyzed by qRT-PCR.
RESULTS: HPV E6/E7 infection affects SPINT2 methylation rate in cell lines. SPINT2 methylation rate of HT-3E6/E7 was 8.8%, while the methylation rate of SPINT2 in HT-3 was 0%. In cervical tissues, the methylation rate of SPINT2 in cervical cancers was 54%, while the methylation rate of SPINT2 in normal cervical samples was 25%. As for cervical cancers, the methylation rate of SPINT2 gene was higher in grade 3 than those of grade 2.
CONCLUSIONS: The expression of SPINT2 gene is regulated by its methylation status, and the methylation status of SPINT2 is altered by HPV infection. The aberrant methylation status of SPINT2 gene may play an important role in the development of cervical cancer.

Fuchs O
Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs.
Cardiovasc Hematol Disord Drug Targets. 2019; 19(1):51-78 [PubMed] Related Publications
Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

Further References

Andrieu V, Radford-Weiss I, Troussard X, et al.
Molecular detection of t(8;21)/AML1-ETO in AML M1/M2: correlation with cytogenetics, morphology and immunophenotype.
Br J Haematol. 1996; 92(4):855-65 [PubMed] Related Publications
The t(8;21) identifies a subgroup of acute myeloid leukaemia (AML) with a relatively good prognosis which may merit different treatment. It is associated predominantly, but not exclusively, with AML M2, and corresponds to rearrangements involving the AML1 and ETO genes. AML1-ETO positive, t(8;21) negative cases are well recognized but their incidence is unknown. In order to determine optimal prospective AML1-ETO RT-PCR screening strategies, we analysed 64 unselected AML M1 and M2 cases and correlated the results with other biological parameters. Molecular screening increased the overall detection rate from 8% to 14%. AML1-ETO was found in 3% (1/32) of AML M1 and 25% (8/32) of M2, including three patients without a classic (8;21) but with chromosome 8 abnormalities. It was more common in younger patients. Correlation with morphology enabled development of a scoring system which detected all nine AML1-ETO-positive cases with a false positive rate of 7% (4/55). Although certain AML1-ETO-positive cases demonstrated characteristic immunological features (CD19 and CD34 expression, CD33 negativity), each of these markers was insufficiently specific to permit prediction in an individual case. We conclude that initial routine prospective molecular screening for AML1-ETO in all AMLs, combined with standardized morphological and immunological analysis, is desirable in order to produce improved prognostic stratification and to determine whether screening can ultimately be restricted to appropriate subgroups.

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