A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes

Careccia, Silvia; Mainardi, Sara; Pelosi, Andrea; Gurtner, Aymone; Diverio, Daniela; Riccioni, Roberta; Testa, Ugo; Pelosi, Elvira; Piaggio, Giulia; Sacchi, Ada; Lavorgna, Serena; Lo‐Coco, Francesco; Blandino, Giovanni; Levrero, Massimo; Rizzo, Maria Giulia

doi:10.1038/onc.2009.255

Cited by 80 publications

(84 citation statements)

References 25 publications

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“…Our in vivo model, describing miR-15b as a tumor suppressor, is substantially consistent with what has previously been observed in other tumors, such as glioma (22), osteosarcoma (10), gastric cancer cells (23), and acute promyelocytic leukemia (8,9). Moreover, it has been reported that miR15b overexpression has a protective role of tumor recurrence after resection of hepatocellular carcinoma (24).…”

Section: Discussionsupporting

confidence: 75%

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miR-15b/16-2 deletion promotes B-cell malignancies

Lovat

Fassan

Gasparini

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over twothirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the wellestablished understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster's role in vivo. These mice developed B-cell malignancy by age 15-18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.miRNAs | miR-15b | chronic lymphocytic leukemia | B cells | murine models M icroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression in many physiological and pathological conditions (1). Altered miRNA expression has been reported in several human cancers, and miRNA expression profiles vary according to the considered tumor (2).A role for miRNAs in tumorigenesis and progression was originally documented for the miR-15/16 family (2-5). This group of miRNAs encompasses the miR-15a/16-1 cluster (on chromosome 13q14,) the miR-15b/16-2 cluster (on chromosome 3q25), and the miR-195/497 cluster (on chromosome 17p13).The role of the miR-15a/16-1 cluster in B-cell pathology has been extensively demonstrated (5). The deletion of the miR-15a/ 16-1 cluster has been reported in over two-thirds of B-cell chronic lymphocytic leukemias (B-CLLs) (5). Our group has demonstrated that the loss of miR-15a/16-1 expression induces higher levels of the antiapoptotic proteins BCL2 and myeloid cell leukemia sequence 1 (BCL2-related) (MCL1) (3, 6). Moreover, this deletion promotes mature B-cell expansion by deregulating the transition from G1 to S phase (7).On the other hand, the biological role of miR-15b/16-2 is still controversial, as this cluster has been reported to behave as either a tumor suppressor [acute promyelocytic leukemia (8, 9) and osteosarcoma (10)] or an oncogene [melanoma (11), upregulated in the plasma of colorectal cancer (12) and...

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Section: Discussionsupporting

confidence: 75%

“…On the other hand, the biological role of miR-15b/16-2 is still controversial, as this cluster has been reported to behave as either a tumor suppressor [acute promyelocytic leukemia (8,9) and osteosarcoma (10)] or an oncogene [melanoma (11), upregulated in the plasma of colorectal cancer (12) and head and neck carcinoma (13)]. …”

mentioning

confidence: 99%

miR-15b/16-2 deletion promotes B-cell malignancies

Lovat

Fassan

Gasparini

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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“…13,[29][30][31] The miR-142-3p expression was reported to increase by 2.5-fold after 2 weeks of granulocytic differentiation in UCB-derived CD34 ϩ cells. 13 A study compared miRNA expression among HSPCs and peripheral blood leukocytes also identified miR-142-3p as the most up-regulated miRNA in peripheral blood leukocytes. 30 Meanwhile, previous reports regarding miR-29a did not demonstrate its involvement in myeloid differentiation but focused on its abnormal expression in many kinds of leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…12 In addition, increased miR-142-3p expression has been observed at different stages of normal granulocytopoiesis. 13 Validated targets of miR-142-3p include ADCY9, 14 CD133, 15 IL-6, 16 and the RAC1. 17 In this study, we sought to investigate role of these 2 miRNAs in monocytic and granulocytic differentiation (also called myeloid differentiation), and to test whether their down-regulation is related to the differentiation block in AML blasts.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Wang

Gong

et al. 2012

Blood

159

148

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IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of blood cancers characterized by increased, uncontrolled proliferation of hematopoietic progenitors, and a blockage in myeloid differentiation is the major characteristic of AML. 1 According to the French-American-British classification system, AMLs involving the monocytic and granulocytic lineage account for 85% (M1 to M5 subtypes) of adult patients. 2 Under normal conditions, monocytes and granulocytes develop from long-term hematopoietic stem cells (LT-HSCs) in BM under the influence of a complex network of cytokins such as G-CSF, GM-CSF, and M-CSF, and transcription factors such as PU.1, C/EBP, IFN consensus sequence binding protein/IFN regulatory factor 8, Krüppel-like factor 4, c-Maf, and C/EBP⑀. [3][4][5][6] MicroRNAs (miRNAs) that negatively regulate gene expression at posttranscriptional level 7 have also been identified as crucial regulators in normal and malignant myeloid differentiation. Expression and function analyses have unraveled their important regulatory roles during hematopoiesis. 8 In a previous study, we demonstrated a significantly decreased expression of miR-29a and 142-3p in the peripheral blood mononuclear cells (PBMNCs) from AML patients (French-AmericanBritish M1 to M5 subtypes). 9 These 2 miRNAs were also reported to be down-regulated in a variety of tumors and to act as tumor suppressors. [10][11][12] The miR-29a cluster is one of the most studied miRNA clusters. Down-regulation of miR-29a was observed in AML samples with deletions of 7q (del7q). 10 Several genes have been reported to be silenced by miR-29, most of which are potential oncogenes, such as SKI, Tcl1, the p53 upstream inhibitors p85a and CDC42, and the Bcl2 family members Bcl2 and Mcl1. 11 Meanwhile, miR-142-3p, first identified as being uniquely expressed in hematopoietic system, is aberrantly expressed in T-cell and B-cell leukemia. 12 In addition, increased miR-142-3p expression has been observed at different stages of normal granulocytopoiesis. 13 Validated targets of miR-142-3p include ADCY9, 14 CD133, 16 and the RAC1. 17 In this study, we sought to investigate role of these 2 miRNAs in monocytic and granulocytic differentiation (also called myeloid differentiation), and to test whether their down-regulation is related to the differentiation block in AML blasts. Using the leukemia cell lines, NB4, HL-60, and THP-1 18-23 we observed up-regulation of miR-29a and miR-142-3p expression during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation and phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and examined effects of overexpression or knockdown of each miRNA on myeloid differentiations. Moreover, we identified targets of both miRNAs and examined direct effect of the target genes on myeloid differentiation. Similar results were also obtained in myeloid induction cultures of CD34 ϩ hematopoietic stem/ progenitor cells (HSPCs) derived from normal human umbilical cord blood (UCB) and BM from healthy donors and AML p...

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“…The human let-7 family contains 13 members located on nine different chromosomes, and is widely viewed as a family of tumorsuppressor miRNAs (6). Consistent with this activity, the expression of several let-7 family members is downregulated in many cancer types when compared with normal tissue and during tumor progression (7)(8)(9)(10)(11)(12). Previously, we found that in acute promyelocytic leukemia (APL; 13), a subtype of acute myelogenous leukemia (AML) bearing the leukemiapromoting PML/RARa fusion protein, let-7c expression was downregulated in APL blasts at diagnosis, compared with in vitro-differentiated normal promyelocytes (11).…”

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confidence: 89%

Dual Promoter Usage as Regulatory Mechanism of let-7c Expression in Leukemic and Solid Tumors

Pelosi

Careccia

Sagrestani

et al. 2014

Molecular Cancer Research

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Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARa fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARa in an all transretinoic acid (ATRA)-sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.

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A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes

Cited by 80 publications

References 25 publications

miR-15b/16-2 deletion promotes B-cell malignancies

miR-15b/16-2 deletion promotes B-cell malignancies

MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Dual Promoter Usage as Regulatory Mechanism of let-7c Expression in Leukemic and Solid Tumors

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