Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia

Wang, Dandan; Zheng, Lichuan; Cheng, Bowie Y.; Sin, Chun-Fung; R, Li; Tsui, Sze Pui; Yi, Xinyu; Hang, Alvin Chun; He, Ben; Leung, Anskar Yu Hung; Sun, Xuan

doi:10.1038/s41388-023-02611-y

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…Interactions between Pink1 and other candidate proteins, such as TP16, TP53, BECN, and RAC1 warrants further investigation. Nevertheless, with the advancement of zebrafish modelling in hematopoiesis and leukemia 38,39 , our study demonstrated the potential of zebrafish model to further investigate the novel role of Pink1 in vertebrate autophagy and hematopoiesis in vivo.…”

Section: Discussionmentioning

confidence: 90%

Loss of PINK1 promotes the expansion of hematopoietic cells via upregulating autophagy

Chen

Chun‐Hang

2023

Preprint

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PTEN-induced putative kinase 1 (PINK1) is a well-characterized regulator of mitochondrial quality control through mitophagy and its mutations are associated with recessive Parkinson’s disease. However, little is known about its functions in normal and malignant hematopoiesis in vertebrates. Here we aim to unravel the roles of PINK1 in definitive hematopoiesis and its underlying mechanisms using zebrafish (Danio rerio). In this study, we utilized CRISPR/Cas9 system to generate pink1 knockout zebrafish model and PINK1-deficient leukemia cell line. We found that pink1 deficiency activated autophagy in hematopoietic cells and promoted definitive hematopoiesis in zebrafish embryos, which can be alleviated by canonical autophagy inhibition. Further, the proteomic and metabolic analysis revealed an elevated expression of cell proliferation markers and enhanced respiration in pink1-deficient zebrafish embryos. On the other hand, PINK1 deficiency also induced autophagy and cell proliferation in human leukemic cells. Therefore, our findings demonstrated that PINK1 functions as a negative regulator of normal and malignant hematopoiesis through the autophagy-mediated pathway.

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Section: Discussionmentioning

confidence: 90%

Loss of PINK1 promotes the expansion of hematopoietic cells via upregulating autophagy

Chen

Chun‐Hang

2023

Preprint

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“…Combination therapy decreased DNA methylation even more than the monotherapy [ 215 ]. FLT3-ITD and IDH2 R172K or IDH2 R140Q double mutated zebrafish model, when treated with quizartinib and enasidenib, showed reduction in the blast population and spleen size [ 226 ]. Treatment of MOLM-14 cells and newly diagnosed and relapsed FLT3-ITD-mutated AML patient–derived cells with quizartinib and azacitidine/decitabine resulted in synergistic growth inhibition.…”

Section: Dna Methylome Modifiers and Their Roles In Flt3-itd Amlmentioning

confidence: 99%

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Tecik,

Adan

2024

Curr. Treat. Options in Oncol.

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Opinion statementThe internal tandem duplication (ITD) mutation of the FMS-like receptor tyrosine kinase 3 (FLT3-ITD) is the most common mutation observed in approximately 30% of acute myeloid leukemia (AML) patients. It represents poor prognosis due to continuous activation of downstream growth-promoting signaling pathways such as STAT5 and PI3K/AKT. Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. However, patients possess generally poor remission rates and acquired resistance when FLT3I used alone. Various factors in patients could cause these adverse effects including altered epigenetic regulation, causing mainly abnormal gene expression patterns. Epigenetic modifications are required for hematopoietic stem cell (HSC) self-renewal and differentiation; however, critical driver mutations have been identified in genes controlling DNA methylation (such as DNMT3A, TET2, IDH1/2). These regulators cause leukemia pathogenesis and affect disease diagnosis and prognosis when they co-occur with FLT3-ITD mutation. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I’s activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients’ mutational status in terms of FLT3 and DNA methlome regulators.

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“…Zebrafish have emerged as a powerful model system to study the etiology of hematological malignancies due to their conserved regulation of normal and malignant hematopoiesis, genetic tractability, and established imaging and pharmacologic techniques [6][7][8][9][10][11][12][13]. Expression of known fusion proteins in the myeloid lineage induces the expansion and clustering of myeloid cells in embryos and in cases where embryos survive, malignancy in adults [10,[14][15][16][17][18][19][20][21][22][23][24][25]. Pharmacological inhibitors are effective in preventing the myeloid proliferation and expansion observed in embryos ectopically expressing human fusion proteins [10,23,26].…”

Section: Introductionmentioning

confidence: 99%

Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos

Belt,

Grant,

Tombes

et al. 2024

PLoS Genet

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Acute myeloid leukemia (AML) accounts for greater than twenty thousand new cases of leukemia annually in the United States. The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes. In this study we investigated the expression of human MLL-ENL and MLL-AF9 in the myeloid lineage of zebrafish embryos. We observed an expansion of MLL positive cells and determined these cells colocalized with the myeloid markers spi1b, mpx, and mpeg. In addition, expression of MLL-ENL and MLL-AF9 induced the expression of endogenous bcl2 and cdk9, genes that are often dysregulated in MLL-r-AML. Co-treatment of lyz: MLL-ENL or lyz:MLL-AF9 expressing embryos with the BCL2 inhibitor, Venetoclax, and the CDK9 inhibitor, Flavopiridol, significantly reduced the number of MLL positive cells compared to embryos treated with vehicle or either drug alone. In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consist with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.

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Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia

Cited by 4 publications

References 48 publications

Loss of PINK1 promotes the expansion of hematopoietic cells via upregulating autophagy

Loss of PINK1 promotes the expansion of hematopoietic cells via upregulating autophagy

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos

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