MiR-125b-2 is a Potential OncomiR on Human Chromosome 21 in Megakaryoblastic Leukemia

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2010 Mar 3

PMID 20194440

Citations 128

Authors

Jan-Henning Klusmann

Zhe Li

Katarina Bohmer

Aliaksandra Maroz

Mia Lee Koch

Stephan Emmrich

Frank J Godinho

Stuart H Orkin

Dirk Reinhardt

Affiliations

Soon will be listed here.

Abstract

Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.

Citing Articles

miR-1915-3p regulates megakaryocytic and erythroid differentiation by targeting SOCS4.

Yuan X, Liu P, Xu L, Liang L, Dong Q, Fan T Thromb J. 2024; 22(1):74.

PMID: 39123189 PMC: 11316338. DOI: 10.1186/s12959-024-00615-6.

Down syndrome-associated leukaemias: current evidence and challenges.

Mason N, Cahill H, Diamond Y, McCleary K, Kotecha R, Marshall G Ther Adv Hematol. 2024; 15:20406207241257901.

PMID: 39050114 PMC: 11268035. DOI: 10.1177/20406207241257901.

Epigenetic regulation of megakaryopoiesis and platelet formation.

Xu B, Ye X, Wen Z, Chen S, Wang J Haematologica. 2024; 109(10):3125-3137.

PMID: 38867584 PMC: 11443398. DOI: 10.3324/haematol.2023.284951.

Aberrant stem cell and developmental programs in pediatric leukemia.

Ling R, Cross J, Roy A Front Cell Dev Biol. 2024; 12:1372899.

PMID: 38601080 PMC: 11004259. DOI: 10.3389/fcell.2024.1372899.

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 expression.

Sessa R, Trombetti S, Bianco A, Amendola G, Catapano R, Cesaro E Open Biol. 2024; 14(2):230319.

PMID: 38350611 PMC: 10864098. DOI: 10.1098/rsob.230319.

References

Li Z, Godinho F, Klusmann J, Garriga-Canut M, Yu C, Orkin S . Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet. 2005; 37(6):613-9. DOI: 10.1038/ng1566. View

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

Jandrig B, Seitz S, Hinzmann B, Arnold W, Micheel B, Koelble K . ST18 is a breast cancer tumor suppressor gene at human chromosome 8q11.2. Oncogene. 2004; 23(57):9295-302. DOI: 10.1038/sj.onc.1208131. View

Klusmann J, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C . Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood. 2008; 111(6):2991-8. PMC: 2265448. DOI: 10.1182/blood-2007-10-118810. View

Shi X, Xue L, Yang J, Ma A, Zhao J, Xu M . An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A. 2007; 104(50):19983-8. PMC: 2148409. DOI: 10.1073/pnas.0706641104. View

Pui J, Allman D, Xu L, DeRocco S, Karnell F, Bakkour S . Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity. 1999; 11(3):299-308. DOI: 10.1016/s1074-7613(00)80105-3. View

Chou S, Opalinska J, Yao Y, Fernandes M, Kalota A, Brooks J . Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood. 2008; 112(12):4503-6. PMC: 2597125. DOI: 10.1182/blood-2008-05-157859. View

Stankiewicz M, Crispino J . ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood. 2009; 113(14):3337-47. PMC: 2665899. DOI: 10.1182/blood-2008-08-174813. View

Li C, Wong W . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A. 2001; 98(1):31-6. PMC: 14539. DOI: 10.1073/pnas.98.1.31. View

10.

Tokumaru S, Suzuki M, Yamada H, Nagino M, Takahashi T . let-7 regulates Dicer expression and constitutes a negative feedback loop. Carcinogenesis. 2008; 29(11):2073-7. DOI: 10.1093/carcin/bgn187. View

11.

Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk N, Bennett P . Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood. 2008; 112(12):4507-11. DOI: 10.1182/blood-2008-04-152967. View

12.

Hasle H . Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol. 2002; 2(7):429-36. DOI: 10.1016/S1470-2045(00)00435-6. View

13.

Xiao C, Calado D, Galler G, Thai T, Patterson H, Wang J . MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007; 131(1):146-59. DOI: 10.1016/j.cell.2007.07.021. View

14.

Carthew R, Sontheimer E . Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136(4):642-55. PMC: 2675692. DOI: 10.1016/j.cell.2009.01.035. View

15.

Viswanathan S, Daley G, Gregory R . Selective blockade of microRNA processing by Lin28. Science. 2008; 320(5872):97-100. PMC: 3368499. DOI: 10.1126/science.1154040. View

16.

Lu J, Guo S, Ebert B, Zhang H, Peng X, Bosco J . MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell. 2008; 14(6):843-53. PMC: 2688789. DOI: 10.1016/j.devcel.2008.03.012. View

17.

Scott G, Goga A, Bhaumik D, Berger C, Sullivan C, Benz C . Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2006; 282(2):1479-86. DOI: 10.1074/jbc.M609383200. View

18.

Sonoki T, Iwanaga E, Mitsuya H, Asou N . Insertion of microRNA-125b-1, a human homologue of lin-4, into a rearranged immunoglobulin heavy chain gene locus in a patient with precursor B-cell acute lymphoblastic leukemia. Leukemia. 2005; 19(11):2009-10. DOI: 10.1038/sj.leu.2403938. View

19.

Le M, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V . MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 2009; 23(7):862-76. PMC: 2666337. DOI: 10.1101/gad.1767609. View

20.

Bourquin J, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P . Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A. 2006; 103(9):3339-44. PMC: 1413912. DOI: 10.1073/pnas.0511150103. View