Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

Togasaki, Emi; Takeda, June; Yoshida, Kenichi; Shiozawa, Yusuke; Takeuchi, Masahiro; Oshima, Motohiko; Saraya, Atsunori; Iwama, Atsushi; Yokote, Koutaro; Sakaida, Emiko; Hirase, Chikara; Takeshita, Akira; Imai, Kiyotoshi; Okumura, Hirokazu; Morishita, Yoshihisa; Usui, Noriko; Takahashi, Naoto; Fujisawa, Shin; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Kiyoi, Hitoshi; Ohnishi, Kazunori; Ohtake, Shigeki; Asou, Norio; Kobayashi, Yasuhito; Miyazaki, Yasushi; Miyano, Satoru; Ogawa, Seishi; Matsumura, Itaru; Nakaseko, Chiaki; Naoe, Tomoki

doi:10.1038/bcj.2017.36

Cited by 49 publications

(36 citation statements)

References 49 publications

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“…1) including a CXXC domain at the amino terminal region that has high affinity for clustered unmethylated CpG dinucleotides and a catalytic domain that is typical of Fe(II)- and 2-OG-dependent dioxygenases (2OGFeDO) [43]. Research indicates that the C-terminal catalytic domain (CD), which belongs to the dioxygenase super family, can oxidize 5-mC in a 2-OG- and Fe(II)-dependent manner.…”

Section: Characteristics Of Tet Family Proteinsmentioning

confidence: 99%

“…In jawed vertebrates, triplication of a common ancestral TET gene led to three different TET paralogs, and a subsequent chromosomal inversion split TET2 gene into two segments encoding catalytic domain and CXXC domain, respectively [43, 45, 46]. Thus, the ancestral CXXC domain of TET2 is now separately encoded by a neighboring gene named IDAX (also known as CXXC4).…”

Section: Characteristics Of Tet Family Proteinsmentioning

confidence: 99%

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Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

2019

Oncol Res Treat

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DNA methylation plays significant roles in a variety of biological and pathological processes including mammalian development, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Recent discoveries indicated that ten-eleven translocation (TET) family of dioxygenases can convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). The TET family includes three members: TET1, TET2, and TET3. With increasing evidence, more and more biological and pathological processes in which 5-hmC and TET family serve unparalleled biological roles are noticed, for example, DNA demethylation and transcriptional regulation of different target genes, which are involved in many human diseases, especially hematologic malignancies, resembling chronic myelomonocytic leukemia, myelodysplastic syndromes, and so on. In this review, we focus on the diverse functions of TET family and the novel epigenetic marks, 5-mC and 5-hmC, in hematologic malignancies. This review will provide valuable insights into the potential targets of hematologic malignancies. Further understanding of the normal and pathological functions of TET family may provide new methods to develop novel epigenetic therapies for treating hematologic malignancies.

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Section: Characteristics Of Tet Family Proteinsmentioning

confidence: 99%

Section: Characteristics Of Tet Family Proteinsmentioning

confidence: 99%

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

2019

Oncol Res Treat

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“…15,16 More recently, specific mutations, especially in epigenetic modifiers, in chronic phase (CP) samples have been linked with an unfavorable TKI response. [17][18][19][20] Mutations in cancer-associated genes at the time of initial diagnosis and their acquisition during treatment are also related to an unfavorable outocome. 19 Nevertheless, knowledge about the prognostic value of genomic data in CML management is still in its infancy.…”

Section: Introductionmentioning

confidence: 99%

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Awad

Kankainen

Ojala³

et al. 2020

Blood Advances

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

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“…Mutations in ASXL1 were originally reported and conferred poor prognosis in MDS [15] and chronic myelomonocytic leukemia (CMMoL) [5]. Frameshift mutations or nonsense mutations in exon 12 of ASXL1 abrogate protein expression [12] and consequently disrupt its function as a tumor suppressor, often in a variety of hematological malignancies [8]. Mutations in ASXL1 contribute to oncogenesis in hematopoietic cells, especially leukemogenesis, and promote myeloid transformation through loss of PRC2-mediated gene repression in MDS and CMMoL [12,16].…”

Section: Discussionmentioning

confidence: 99%

“…Originally identified from sequence analysis of myelodysplastic syndrome (MDS) patients [5], mutations in ASXL1 were a nonspecific genetic abnormality, associated with poor prognosis not only in MDS [6] but also in bcr-abl-negative myeloproliferative neoplasms [6]. Mutations in ASXL1 have been found in the accelerated phase or blast phase [7] and in CML-chronic phase (CP) [8]. Surprisingly, several ASXL1 mutations have also been reported in healthy people [9][10][11], indicating the pleiotropic nature of ASXL1.…”

Section: Introductionmentioning

confidence: 99%

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

et al. 2020

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Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22) (q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk.The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

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Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

Cited by 49 publications

References 49 publications

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

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