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Editorials
   References
1. Engler JR, Frede A, Saunders VA, Zannettino AC, Hughes TP, White DL. Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity. Leukemia. 2010;24(4):765-770.
2. CarterBZ,MakPY,MuH,etal.CombinedinhibitionofMDM2and Bcr-Abl tyrosine kinase targets chronic myeloid leukemia stem/prog- enitor cells in a murine model. Haematologica. 2020;105(5):1274- 1284.
3. Carter BZ, Mak PY, Mu H, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8(355):355ra117.
4. Lau LM, Nugent JK, Zhao X, Irwin MS. HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene. 2008;27(7):997-1003.
5. Willis SN, Chen L, Dewson G, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only pro- teins. Genes Dev. 2005;19(11):1294-1305.
6. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009;114(24):5034-5043.
7. Hunter AM, Sallman DA. Current status and new treatment approaches in TP53 mutated AML. Best Pract Res Clin Haematol. 2019;32(2):134-144.
8. Carter BZ, Mak PY, Mak DH, et al. Synergistic effects of p53 activa- tion via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid
leukemia blast crisis cells. Oncotarget. 2015;6(31):30487-30499.
9. Inoue A, Kobayashi CI, Shinohara H, et al. Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence. Int J Hematol. 2018;108(4):365-
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10. Peterson LF, Mitrikeska E, Giannola D, et al. p53 stabilization
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 1174
Role of Meningioma 1 for maintaining the transformed state in MLL-rearranged acute myeloid leukemia: potential for therapeutic intervention?
Juerg Schwaller
University Children’s Hospital beider Basel (UKBB), Department of Biomedicine (DBM), University of Basel, Switzerland E-mail: JUERG SCHWALLER - j.schwaller@unibas.ch
doi:10.3324/haematol.2019.246348
Meningioma 1 (MN1) was cloned from a bal- anced chromosomal translocation in a menin- gioma as open reading frame encoding for a protein of 1,319 amino acids containing several proline and histidine-rich domains, acting as a transcriptional activator necessary for normal development of the bones of the skull.1,2 Several studies found mutations or aber- rant expression of MN1 in various hematologic malig- nancies. Characterization of a t(12;22)(p13;q11) chromo- somal translocation associated with myeloproliferative disorders revealed a fusion between MN1 and the ETS- family transcription factor ETV6 (a.k.a. TEL).3 A fusion of MN1 to Friend leukemia virus integration 1 (FLI1) has been shown to be a rare transforming oncogene in acute megakaryoblastic leukemia (AMKL).4 Aberrant high expression of MN1 was reported in acute myeloid leukemia (AML) with inv(16) leading to the core-binding factor fusion CBFB-MYH11.5 Clinical studies proposed that high MN1 transcript levels could be used as prog- nostic marker in cytogenetically-normal (CN) AML.6 Functional studies in mice demonstrated the oncogenic potential of aberrant MN1 expression. Retroviral MN1 overexpression in murine bone marrow (BM) hematopoietic stem and progenitor cells (HSPC) fol- lowed by transplantation rapidly induced a lethal AML
in mice.7 Aberrant MN1 expression due to retroviral insertion was shown to act as collaborative oncogenic event in acute leukemia induction by the MLL-ENL or the MLL-AF9 fusion gene, respectively.8,9 More recent work suggested that gene expression programs associat- ed with MN1-mediated transformation of hematopoietic cells are controlled by the H3K4 and H3K79 histone methyltransferases MLL1 and DOT1L, respectively.10 Collectively, these studies indicated that aberrant MN1 expression contributes to malignant transformation of hematopoietic cells towards AML; however, its role in the maintenance of the transformed state remained poorly understood.
In a study published in this issue of Haematologica, Sharma et al. functionally addressed the role of MN1 in the maintenance of AML induced by MLL fusion onco- genes.11 They used Crisper/CAS9 to ablate MN1 in several murine AML lines, including cells transformed by retrovi- ral overexpression of the MLL-AF9 fusion (rMLL-AF9), and in human THP1 and MV4;11 AML cell lines carrying the MLL-AF9 and MLL-AF4 fusions, respectively. They found that inactivation of MN1 impaired the clonogenic activity and proliferation associated with impaired cell cycle progression, and increased differentiation and apop- tosis of murine rMLL-AF9 AML cells. Loss of MN1 also
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