Page 143 - Haematologica May 2020

MLL-rearranged AML requires MN1
Discussion
Acute myeloid leukemia pathogenesis requires a multi- tude of genetic and epigenetic alterations for its initiation and progression.1 One such genetic alteration is high
expression of MN1, which is widely reported as an inde- pendent poor prognostic marker in AML patients, and its induced overexpression in mouse cells induces aggressive AML.7-9,12,13,23 In the knockout studies of MN1, mice died young from cleft palate and severe defects in development
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Figure 7. Meningioma 1 (MN1) as therapeutic target in MLL-AF9 acute myeloid leukemia (AML). (A) Colony-forming cell (CFC) counts of CD34+ healthy controls (Ctrl) and MLL-AF9 positive AML patient cells treated with anti-MN1 siRNA/LNP formulation normalized to control siRNA/lipid nanoparticle (LNP) formulation [mean±stan- dard error of mean (SEM), cells from n=4 CD34+ healthy donors with 3 repeats, and cells from n=4 MLL-AF9 positive AML patients with 4 repeats and 2 repeats from 1 patient]. (B) Morphology of representative CFC colonies of CD34+ healthy controls and MLL-AF9 positive AML patient cells treated with control or anti-MN1 siRNA/LNP formulation. Black scale bar represents 0.25mm. (C) Number of viable cells from colonies of CD34+ healthy controls and MLL-AF9 positive AML patient cells treated with anti-MN1 siRNA/LNP formulation normalized to control siRNA/LNP treated cells (mean±SEM, cells from n=1 CD34+ healthy donor in triplicate, and cells from n=4 MLL-AF9 positive AML patients in duplicate from each patient). *P<0.05; **P<0.01; ns: not significant. (D) Model of MN1-dependency in MLL- rearranged AML. MLL-AF9 and MN1 induces expression of HOXA cluster genes and MEIS1. MN1 is a critical co-factor of the HOXA9/MEIS1 transcriptional complex. Loss of MN1 affects HOXA expression and renders the HOXA9/MEIS1 complex inactive, and loss of this critical downstream complex of MLL-AF9 blocks its transform- ing ability.
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