The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

Toki, Tsutomu; Kanezaki, Rika; Adachi, Souichi; Fujino, Hisanori; Xu, Gang; Sato, Tomohiko; Suzuki, Kazuhiro; Tauchi, Hisamichi; Ito, Etsuro

doi:10.1038/leu.2008.267

Cited by 19 publications

(14 citation statements)

References 27 publications

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“…To directly test whether TL-blasts can fulfill this intrinsic eosinophil program during differentiation, we cultured sorted TL-blasts from three patients (for GATA1s status see Supplementary Table 1) in medium containing G-CSF, GM-CSF, IL3 and SCF (40). Under these culture conditions, normal CD34 + -hematopoietic stem and progenitor cells (HSPCs) differentiate into monocytes and granulocytes (Figure 2b and 3c–d) (41).…”

Section: Resultsmentioning

confidence: 99%

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

et al. 2013

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Transient leukemia (TL) is evident in 5–10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we report that TL cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s-mutation as sorted TL-blasts, consistent with their clonal origin. TL-blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. ChIP-seq indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1Δe2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.

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Section: Resultsmentioning

confidence: 99%

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

et al. 2013

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“…Therefore, we tried to search mutations of TRIB1 in cases of ML-DS and TL in which such mutations are infrequent. 9 In a case of DS-AMKL (case 84), a nucleotide change from guanine to thymine has been identified at 902 that results in amino acid alteration from arginine 107 (R107) to leucine ( Figure 1B). The sequence changes were confirmed by subcloning the PCR product into the TA-type plasmid vector (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia

Yokoyama

Toki

Aoki

et al. 2012

Blood

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Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome-related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBP␣ degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome-related acute megakaryocytic leukemia. (Blood. 2012; 119(11):2608-2611) IntroductionThe Down syndrome (DS) patients are predisposed to developing myeloid leukemia, and those patients frequently exhibit GATA1 mutations. 1 However, it is proposed that the GATA1 mutation is important for transient leukemia in DS but not sufficient for full-blown leukemia, suggesting that additional genetic alterations are needed. 1 Therefore, it is important to search the subsequent genetic changes for DS-related leukemia (ML-DS) to predict malignant transformation and prognosis of the patients.Trib1 has been identified as a myeloid oncogene that cooperates with Hoxa9 and Meis1 in murine acute myeloid leukemia (AML). 2 As a member of the tribbles family of proteins, TRIB1 interacts with MEK1 and enhances ERK phosphorylation. 2,3 Moreover, TRIB1 promotes degradation of C/EBP family transcription factors, including C/EBP␣, an important tumor suppressor for AML, and we observed that degradation of C/EBP␣ by Trib1 is mediated by its interaction with MEK1. 4 Thus, TRIB1 plays an important role in the development of AML by modulating both the RAS/MAPK pathway and C/EBP␣ function together with Trib2 that has also been identified as a myeloid-transforming gene. 5 Potential involvement of TRIB1 in human leukemia has been reported in cases of AML with 8q34 amplification in which both c-MYC and TRIB1 are included in the amplicon. 6 The enhancing effect of TRIB1 on the MAPK signaling suggests that TRIB1 alterations may be related to AML cases, which do not show any mutations in the pathway members, such as FLT3, c-Kit, or Ras. In this report, we identified a novel somatic mutation of TRIB1 in a case of human acute megakaryocytic leukemia developed in DS (DS-AMKL). Retrovirus-mediated gene transfer followed by bone marrow transfer indicated that the mutation enhanced leukemogenic activity and MAPK phosphorylation by TRIB1. Patient 84 showed trisomy 21 and extensive leukocytosis at birth. Hematologic findings revealed the white blood cell count to be 148 ϫ 10 9 /L, including 87% myeloblasts, a hemoglobin level of 19.4 g/dL, and a platelet count of 259 ϫ 10 9 /L. Patent ductus arteriosus and atrial septal defect...

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“…KIT is a Sox2 enhancer-interacting gene assayed by 4C-seq (circular chromosome conformation capture) in human embryonic stem cells (28). Previous research indicated that KIT promotes proliferation and invasion by activating the PI3K-AKT pathway in some human carcinomas (29,30). For this reason, we wondered whether miR-200c participates in the growth and metastasis of CRCs through the PI3K-Akt pathway.…”

Section: Mir-200cmentioning

confidence: 99%

Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an miR-200c-Sox2–Negative Feedback Loop Mechanism

Xue

et al. 2014

Clinical Cancer Research

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Purpose: To elucidate a novel mechanism of miR-200c in the regulation of stemness, growth, and metastasis in colorectal carcinoma (CRC).Experimental Design: Quantitative reverse transcription PCR was used to quantify miR-200c expression in CRC cell lines and tissues. A luciferase assay was adopted for the target evaluation. The functional effects of miR-200c in CRC cells were assessed by its forced or inhibited expression using lentiviruses.Results :

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The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

Cited by 19 publications

References 27 publications

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia

Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an miR-200c-Sox2–Negative Feedback Loop Mechanism

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