miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Bousquet, Marina; Zhuang, Guoqing; Ma, Cong; Ying, Wei; Cheruku, Patali S.; Shie, Andrew T.; Wang, Stephanie; Ge, Guangtao; Wong, Piu; Wang, Gang; Safe, Stephen; Zhou, Beiyan

doi:10.1158/1541-7786.mcr-13-0002-t

Cited by 34 publications

(33 citation statements)

References 48 publications

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“…Recent work has shown that KLF4 is an important transcription factor whose expression is low or absent in AML cases with high CDX2 expression (16) and that the loss of miR-150 expression leads to increased proliferation, decreased apoptosis, and inhibited differentiation in AML (22)(23)(24). Our work now demonstrates that KLF4 expression is decreased in a large proportion of AML cases irrespective of most cytogenetic abnormalities.…”

Section: Discussionsupporting

confidence: 61%

“…Previously, we showed that miRNA 150 (miR-150) expression is low or absent in pediatric and adult AML patient samples across various cytogenetic and molecular risk groups and in normalkaryotype (NK) AML cases, suggesting that miR-150 loss occurs pervasively in AML (22)(23)(24). In AML primary patient samples and cell lines, we demonstrated that expression of miR-150 decreases cell proliferation and promotes myeloid differentiation (22).…”

mentioning

confidence: 93%

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Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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bAcute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.A cute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem or progenitor cells and a failure of differentiation to mature myeloid cells. Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1, 2), which are altered in AML (3-5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5). This family includes 17 different isoforms that bind to GCrich regions of DNA via three zinc finger domains and regulate the transcriptional activity of target genes by using two glutaminerich transactivation domains (5). KLF4 regulates differentiation of epidermal and vascular smooth muscle cells (6, 7), as well as cellular reprogramming to induce pluripotent stem cells (8). In normal hematopoiesis, KLF2 and KLF4 regulate myeloid differentiation and KLF4 expression induces CDKN1A (p21), which contributes to cell cycle arrest (9-13). In T-cell acute lymphoblastic leukemia (T-ALL) (14) and B-cell lymphomas, KLF4 has been described as a tumor suppressor regulating proliferation, apoptosis, and differentiation (15). A recent study showed that the homeobox transcription factor CDX2 represses KLF4 in myeloid leukemia cells (16). The investigators also observed that C...

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Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 93%

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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“…Genes crucial for lactation, such as miR-150-5p predicted targets Elovl5 and Fads1, are expressed at low levels until late pregnancy when they increase coincident with the decline of miR-150-5p. Conversely, validated miR-150 targets Egr2 (Bousquet et al, 2013) and Myb (Xiao et al, 2007) decreased at mid-pregnancy when miR-150 increased (Fig. S2B).…”

Section: Decreased Expression Of Mirnas Between Late Pregnancy and Eamentioning

confidence: 96%

Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis

et al. 2016

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Profiling of RNA from mouse mammary epithelial cells (MECs) isolated on pregnancy day (P)14 and lactation day (L)2 revealed that the majority of differentially expressed microRNA declined precipitously between late pregnancy and lactation. The decline in miR-150, which exhibited the greatest fold-decrease, was verified quantitatively and qualitatively. To test the hypothesis that the decline in miR-150 is crucial for lactation, MEC-specific constitutive miR-150 was achieved by crossing ROSA26-lox-STOP-lox-miR-150 mice with WAP-driven Cre recombinase mice. Both biological and foster pups nursed by bitransgenic dams exhibited a dramatic decrease in survival compared with offspring nursed by littermate control dams. Protein products of predicted miR-150 targets Fasn, Olah, Acaca, and Stat5B were significantly suppressed in MECs of bitransgenic mice with constitutive miR-150 expression as compared with control mice at L2. Lipid profiling revealed a significant reduction in fatty acids synthesized by the de novo pathway in L2 MECs of bitransgenic versus control mice. Collectively, these data support the hypothesis that a synchronized decrease in miRNAs, such as miR-150, at late pregnancy serves to allow translation of targets crucial for lactation.

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“…This event is due to myeloproliferation and decrease of erythropoiesis. SHIP1 downregulation results in activation of IL-6 signaling pathway and induces a reactive proliferation of the relatively apoptosis-resistant myeloid precursor cells [49,73]. …”

Section: Mirna-29mentioning

confidence: 99%

“…Group 1 characterized with high level of expression of sncRNAs, which associated with sensitivity to therapy. This group members are miRNA-181a, b; let-7f, miRNA-9*, miRNA-96, miRNA-135a, miRNA-409, miRNA-10, miRNA29b and miRNA-217 [72,73,[97][98][99][100]. Group 1 members act through activation of cellular differentiation, inhibition of leukemic cells proliferation and survival, regulation of cell cycle, inducing of apoptosis and suppression of migration and invasion.…”

Section: Sncrnas As Markers Of Therapeutic Resistance or Sensitivity mentioning

confidence: 99%

Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid Leukemia

Klimenko¹

2018

Myeloid Leukemia

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Small non-coding RNAs (sncRNAs) are small regulatory molecules, which play key roles in fine-tune of all cell functions. In late 1970s and early 1980s, it was first determined that non-coding RNAs contribute to the cellular regulatory processes. The kingdom of sncRNAs is very numerous and it is clear that functions of different members of this family is different from each other and may be involved in normal and pathologic processes in cell. Recently it was investigated that sncRNAs and long non-coding RNAs play roles in cellular differentiation, proliferation, metabolic processes, bioenergetic regulation, cell death and inter-cellular communications, etc. In embryos, non-coding RNAs control maternal-zygotic transition, the maintenance of pluripotency, the pattering of the body axes, the specification and differentiation of cell types and morphogenesis of organs. Development of hematologic malignancies in humans, their course and regulation of resistance and sensitivity of tumorous cells to therapy are under the control of sncRNAs.

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miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Cited by 34 publications

References 48 publications

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis

Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid Leukemia

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