Pathogenesis of <i>ETV6/RUNX1</i>-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

Sun, Congcong; Chang, Lixian; Zhu, Xiaofan

doi:10.18632/oncotarget.16367

Cited by 57 publications

(41 citation statements)

References 120 publications

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“…In the case of ETV6-RUNX1, the leukemia-inducing potential of the fusion seems to be very low. This is in accordance with (1) the low concordance rate of 10% in identical twins, 18 (2) the long postnatal latency phase (2-14 years), 2 (3) the presence of recurrent secondary leukemia inducing genetic lesions (ETV6 deletions in 70%, extra copies of RUNX1 in 23%, or extra der(21)t (12;21) in 10% of cases), 19 and (4) evidence from transgenic animal studies. 20 These results strengthen the importance of environmentally or spontaneously caused secondary hits in ETV6-RUNX1 1 ALL.…”

supporting

confidence: 83%

Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

Schafer

Olsen

Laehnemann

et al. 2018

Blood

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supporting

confidence: 83%

Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

Schafer

Olsen

Laehnemann

et al. 2018

Blood

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“…Recent studies suggest that E/R is responsible for the initiation of leukaemia and is also essential for disease progression and maintenance, through deregulation of different molecular pathways that contribute to leukemogenesis. E/R regulates phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway, which promotes proliferation, cell adhesion and DNA damage response; STAT3 pathway involved in self-renewal and cell survival and MDM2/TP53 whose deregulation induces the inhibition of apoptosis and consequently cell survival [11].…”

Section: Introductionmentioning

confidence: 99%

ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia

Montaño

Ordóñez

Alonso-Pérez

et al. 2020

Cells

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Background: The t(12;21)(p13;q22), which fuses ETV6 and RUNX1 genes, is the most common genetic abnormality in children with B-cell precursor acute lymphoblastic leukaemia. The implication of the fusion protein in leukemogenesis seems to be clear. However, its role in the maintenance of the disease continues to be controversial. Methods: Generation of an in vitro ETV6/RUNX1 knock out model using the CRISPR/Cas9 gene editing system. Functional characterization by RNA sequencing, proliferation assays, apoptosis and pharmacologic studies, and generation of edited-cell xenograft model. Results: The expression of ETV6/RUNX1 fusion gene was completely eliminated, thus generating a powerful model on which to study the role of the fusion gene in leukemic cells. The loss of fusion gene expression led to the deregulation of biological processes affecting survival such as apoptosis resistance and cell proliferation capacity. Tumour cells showed higher levels of apoptosis, lower proliferation rate and a greater sensitivity to PI3K inhibitors in vitro along as a decrease in tumour growth in xenografts models after ETV6/RUNX1 fusion gene abrogation. Conclusions: ETV6/RUNX1 fusion protein seems to play an important role in the maintenance of the leukemic phenotype and could thus become a potential therapeutic target.

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“…This “two-hit” theory was already described almost 50 years ago by Knudson et al . 48 , many research groups have based their work on this theory 49–52 , and Molony leukemia virus insertions in genes such as Evi1 in the NRAS G12D mouse result in acute leukemia 16 . To explore “two-hit” for RASGRP1 overexpression we plotted co-occurrence for the top 8 SL3-3 leukemia virus insertion sites in our previously reported mouse leukemia screen 4 .…”

Section: Discussionmentioning

confidence: 99%

Increased baseline RASGRP1 signals Enhance Stem Cell Fitness during Native Hematopoiesis

Karra

Romero‐Moya

Ksionda

et al. 2020

Preprint

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24Oncogenic mutations in RAS genes, like KRAS G12D or NRAS G12D , trap Ras in the active 25 state and cause myeloproliferative disorder and T cell leukemia (T-ALL) when induced 26 4 Keywords 43 Leukemia, bone marrow, T-ALL, RAS signaling, RASGRP1, cytokines, progenitor, stem 44 cells, hematopoiesis 45 46 47 5 48 49 Acute lymphoblastic leukemia (ALL) is an aggressive bone marrow (BM) malignancy. 50Approximately 15% of pediatric and 25% of adult cases of ALL are diagnosed as T-cell 51 ALL (T-ALL) cog. In the clinic, T-ALL patients receive combination chemotherapy, 52 sometimes combined with BM transplantation 2 . Understanding the molecularly altered 53 biochemical pathways implicated in T-ALL is critical to developing effective molecular 54 therapy (precision medicine). One commonly affected pathway is the RAS pathway with 55 roughly 50% of all patient T-ALL cases demonstrating hyperactive RAS signals in the 56 BM 3 . There are two major mechanisms of leukemogenic RAS signals in T-ALL patients; 57 the first consists of somatic activating mutations of small RAS GTPases themselves and 58 a second mechanism is through deregulated overexpression of the RAS activator 59 RASGRP1 (RAS guanine nucleotide releasing protein 1) 4,5 . 60 61Oncogenic mutations in RAS are among the most common somatic mutations in 62 cancer. Mutations in glycine at codon 12 in KRAS (KRAS G12 ) are prevalent in cancer 63 and result in severely impaired GTPase activity and elevated levels of constitutively 64 active, GTP-bound KRAS 6 . In hematopoietic malignancies, mutations in NRAS are 2 to 65 3 times more frequent than those in KRAS 7,8 , including pediatric T-ALL 9 . Generation of 66 Kras G12D mice aided the field of cancer research and oncogenic RAS signaling; these 67 mice express a mutation of glycine to aspartic acid at codon 12 from the endogenous 68Kras locus in a controlled and inducible manner via a LoxP-STOP-LoxP cassette 6 . In 69 BM cells, oncogenic KRAS G12D can be inducibly expressed using Mx1CRE transgenic 70 6 mice; in this model CRE is expressed from the IFN-α/β-inducible Mx1 promoter by 71 administration of polyinosinic-polycytidylic acid (pIpC) 10 . Such KRAS G12D mice develop 72 a lethal myeloproliferative disease (MPD) resulting in death around 35 days 11,12 . In the 73 background a T-ALL exists, which is suppressed by the MPD, but can be revealed via 74 transplantation of KRAS G12D hematopoietic stem cells into irradiated recipient mice [12][13][14] . 75Mx1CRE-driven NRAS G12D mutation does not lead to acute MPD 15 . Instead mice 76 develop a chronic myeloproliferative disorder and succumb to hematological disease by 77 15 months on a C57Bl/6 x 129/Sv.jae background but displaying a median survival of 78 588 days on a C57Bl/6 background 16 . 79 80We reported deregulated overexpression of the RAS guanine nucleotide exchange 81 factor RASGRP1 in T-ALL patients 4,5 . RASGRP1 has a growth promoting role in T-cell 82 leukemia 4 and skin cancer 17 . RASGRP1 overexpression through retroviral transduction 83 or via transgenic e...

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Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

Cited by 57 publications

References 120 publications

Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia

Increased baseline RASGRP1 signals Enhance Stem Cell Fitness during Native Hematopoiesis

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