Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia

He, Ben; Shi, Xiangguo; Man, Cheuk Him; C.H., Alvin; Ekker, Stephen C.; Chow, Howard C.H.; So, Chi Wai Eric; Choi, William W.L.; Zhang, Wenqing; Zhang, Yiyue; Leung, Anskar Y. H.

doi:10.1182/blood-2013-02-486688

Cited by 53 publications

(52 citation statements)

References 50 publications

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“…As a molecule controlling important cellular processes such as the growth, proliferation and survival of HSPCs, FLT3 is involved in the pathogenesis of AML. 25–28 We therefore investigated the human CBL-FLT3 pathway in the 293T cell line because no appropriate agents were available for similar studies in zebrafish. 293T cells were transiently transfected to express FLT3 with WT c-CBL or c-CBL-H398Y.…”

Section: Resultsmentioning

confidence: 99%

A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease

Peng

Dong

et al. 2015

Leukemia

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Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14–15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs.

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Section: Resultsmentioning

confidence: 99%

A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease

Peng

Dong

et al. 2015

Leukemia

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“…34 Quantitative reverse-transcription PCR (qRT-PCR) was performed using the StepOnePlus Real-time PCR system (Applied Biosystems Inc.) with a SYBR Green master mix. Analysis was performed in triplicate by the 2 2DDC(T) method and b-actin was used as the housekeeping gene.…”

Section: Qrt-pcrmentioning

confidence: 99%

Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish

Shi

Alvin

et al. 2015

Blood

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Key Points• Zebrafish idh1 plays an important role in the regulation of myelopoiesis and definitive hematopoiesis.• Expression of human IDH1-R132H and its zebrafish orthologue induced an increase in myelopoiesis and 2-hydroxyglutrate.Isocitrate dehydrogenase 1 mutation (IDH1-R132H) was recently identified in acute myeloid leukemia with normal cytogenetics. The mutant enzyme is thought to convert a-ketoglutarate to the pathogenic 2-hydroxyglutarate (2-HG) that affects DNA methylation via inhibition of ten-eleven translocation 2. However, the role of wild-type IDH1 in normal hematopoiesis and its relevance to acute myeloid leukemia is unknown. Here we showed that zebrafish idh1 (zidh1) knockdown by morpholino and targeted mutagenesis by transcription activator-like effector nuclease might induce blockade in myeloid differentiation, as evident by an increase in pu.1 and decrease in mpo, l-plastin, and mpeg1 expression, and significantly reduce definitive hematopoiesis. Morpholino knockdown of zidh2 also induced a blockade in myeloid differentiation but definitive hematopoiesis was not affected. The hematopoietic phenotype of zidh1 knockdown was not rescuable by zidh2 messenger RNA, suggesting nonredundant functions. Overexpression of human IDH1-R132H or its zebrafish ortholog resulted in 2-HG elevation and expansion of myelopoiesis in zebrafish embryos. A human IDH1-R132H-specific inhibitor (AGI-5198) significantly ameliorated both hematopoietic and 2-HG responses in human but not zebrafish IDH1 mutant expression. The results provided important insights to the role of zidh1 in myelopoiesis and definitive hematopoiesis and of IDH1-R132H in leukemogenesis. (Blood. 2015;125(19):2974-2984

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“…We concluded that FLT3-ITD-expressing myeloid cells arose in the KM, and immature blast cells progressively infiltrated the KM before being circulated into the PB. Recently, He et al 15 reported that ubiquitous expression of FLT3 had important roles in primitive and definitive hematopoiesis during the embryonic development of zebrafish. They also demonstrated that expressing human FLT3-ITD in zebrafish embryos resulted in myeloid cells expansion and clustering.…”

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confidence: 99%

“…They also demonstrated that expressing human FLT3-ITD in zebrafish embryos resulted in myeloid cells expansion and clustering. 15 However, they didn't examine the phenotype of FLT3-ITD expression in adult zebrafish. In the present study, we expressed the FLT3-ITD in spi-1-positive cells and demonstrated some leukemia phenotype at the age of 9 months.…”

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confidence: 99%

Overexpression of FLT3-ITD driven by spi-1 results in expanded myelopoiesis with leukemic phenotype in zebrafish

Hou

et al. 2016

Leukemia

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Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia

Abstract: Key Points• Zebrafish flt3 plays an important role in the initiation of definitive hematopoietic stem cells.

Cited by 53 publications

References 50 publications

A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease

A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease

Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish

Overexpression of FLT3-ITD driven by spi-1 results in expanded myelopoiesis with leukemic phenotype in zebrafish

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