Hematopoietic regulation by microRNAs
MicroRNAs (miRNAs) are short, 20 to 25 nucleotide non-coding RNAs that garnered broad attention as master post-transcriptional regulators of gene expression. A single miRNA often targets many messenger RNAs, and can thus orchestrate individual pathways at multiple levels or many different pathways simultaneously. In recent years, miRNAs have been established as key players in developmental and physiological processes, as well as in pathological ones such as cancer. They have further been identified as potential therapeutic targets in a number of cancers, and miRNA-based treatment strategies are already undergoing clinical trials.
MiRNAs are therefore an enduring topic of interest in our research, for their roles in healthy blood formation and leukemic transformation. We previously showed that the miR-99a/105~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis, and are now investigating their deregulation. Our group has also found the miR-193 family members to be potent tumor suppressors and biomarkers in adult and pediatric AMLs.
We identified four miR-193 targets within the MAPK pathway, which is frequently dysregulated in cancer including AML. By targeting multiple levels of this pathway, miR-193 mimics may represent a more effective treatment option compared to drugs that have so far been unsuccessful in clinical trials.
Endogenous tumor suppresor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia.
Bhayadia R, Krowiorz K, Haetscher N, Jammal R, Emmrich S, Obulkasim A, Fiedler J, Schwarzer A, Rouhi A, Heuser M, Wingert S, Bothur S, Döhner K, Mätzig T, Ng M, Reinhardt D, Döhner H, Zwaan CM, van den Heuvel Eibrink M, Heckl D, Fornerod M, Thum T, Humphries RK, Rieger MA, Kuchenbauer F, Klusmann JH.
J Clin Oncol. 2018 Feb 12;0(0):0. doi: 10.1200/JCO.2017.75.2204.
miR-139-5p controls translation in myeloid leukemia through EIF4G2.
Emmrich S, Engeland F, El-Khatib M, Henke K, Obulkasim A, Schöning J, Katsman-Kuipers JE, Michel Zwaan C, Pich A, Stary J, Baruchel A, de Haas V, Reinhardt D, Fornerod M, van den Heuvel-Eibrink MM, Klusmann JH.
Oncogene. 2016 Apr 7;35(14):1822-31. doi: 10.1038/onc.2015.247.
miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling.
Emmrich S, Rasche M, Schöning J, Reimer C, Keihani S, Maroz A, Xie Y, Li Z, Schambach A, Reinhardt D, Klusmann JH.
Genes Dev. 2014 Apr 15;28(8):858-74. doi: 10.1101/gad.233791.113.
miR-9 is a tumor suppressor in pediatric AML with t(8;21).
Emmrich S, Katsman-Kuipers JE, Henke K, Khatib ME, Jammal R, Engeland F, Dasci F, Zwaan CM, den Boer ML, Verboon L, Stary J, Baruchel A, de Haas V, Danen-van Oorschot AA, Fornerod M, Pieters R, Reinhardt D, Klusmann JH, van den Heuvel-Eibrink MM.
Leukemia. 2013 Dec 20;28(5):1022-32. doi: 10.1038/leu.2013.357.
miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia.
Klusmann JH, Li Z, Böhmer K, Maroz A, Koch ML, Emmrich S, Godinho FJ, Orkin SH, Reinhardt D.
Genes Dev. 2010 Mar 1;24(5):478-90. doi: 10.1101/gad.1856210.