Page 134 - Haematologica May 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1294-1305
Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia
Amit Sharma,1 Nidhi Jyotsana,1 Razif Gabdoulline,1 Dirk Heckl,2
Florian Kuchenbauer,3 Robert K. Slany,4 Arnold Ganser1 and Michael Heuser1
1Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 2Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 3British Columbia Cancer
4
Agency, Vancouver, British Columbia, Canada and Department of Genetics, Friedrich-
Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Acute Myeloid Leukemia
ABSTRACT
Mixed lineage leukemia (MLL/KMT2A) rearrangements (MLL-r) are one of the most frequent chromosomal aberrations in acute myeloid leukemia. We evaluated the function of Meningioma 1 (MN1), a co-factor of HOXA9 and MEIS1, in human and murine MLL- rearranged leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL positive murine and human leukemia cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-rearranged cells. Expression analysis and chromatin immunoprecipitation with sequencing from previously reported data sets demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin. Treatment of MLL-rearranged primary leukemia cells with anti- MN1 siRNA significantly reduced their clonogenic potential in contrast to normal CD34+ hematopoietic progenitor cells, suggesting a therapeutic window for MN1 targeting. In summary, our findings demonstrate that MN1 plays an essential role in MLL fusion leukemias and serve as a thera- peutic target in MLL-rearranged acute myeloid leukemia.
Introduction
Acute myeloid leukemia (AML) is associated with a plethora of genetic alterations such as chromosomal rearrangements and mutations,1 with some of them being generic for different types of leukemias and cancers.1 MLL1 (Mixed lineage leukemia 1/KMT2A) rearrangements are one such example that are found in myeloid as well as lymphoid leukemias.2 Approximately 135 different MLL rearrangements have been identified so far, but only nine specific gene fusions (including AF4, AF9, ENL, and AF6) account for more than 90% of all oncogenic recombinations.3,4 A unifying hallmark of all MLL-rearranged (MLL-r) leukemias is the deregulation of clustered HOXA/MEIS1 genes.2 Transcriptional activation of MLL target genes (HOXA9/MEIS1) is associated with an increase in histone H3 lysine79 dimethylation (H3K79me2) across the respective gene locus, which is specifically mediated by his- tone methyltransferase DOT1.2,5 Recently, several studies in patients and murine models have highlighted the importance of co-operating genetic alterations in MLL- r leukemia progression. In 40-50% of MLL-r AML cases, RAS and FLT3 mutations have been shown to accelerate leukemogenesis, and Mn1, Bcl11a and Fosb have been identified as co-operating oncogenes in a murine leukemia virus insertional mutage- nesis model.4,6
MN1 (Meningioma-1) is frequently over-expressed in AML patients and is associat- ed with a poor prognosis.7-13 However, in patients with inv(16), highest MN1 expres- sion has been reported with favorable prognosis to current therapeutics.11 MN1 func- tions as a transcriptional regulator that co-operates with the nuclear receptors for retinoic acid (RAR) and vitamin D, by acting as co-activator or co-repressor, depend- ing on the interacting partners.14-16 In addition, MN1 is frequently over-expressed and occasionally fused to TEL as part of the rare MN1-TEL translocation.17 Mn1 is known
Correspondence:
MICHAEL HEUSER
heuser.michael@mh-hannover.de
Received: November 6, 2018. Accepted: August 8, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2018.211201
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