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Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia

Amit Sharma1, Nidhi Jyotsana1, Razif Gabdoulline1

  • 1Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Haematologica
|August 16, 2019
PubMed

Insights

Meningioma 1 (MN1) is crucial for MLL-rearranged acute myeloid leukemia development. Targeting MN1 inhibits leukemia cell growth and promotes differentiation, offering a potential therapeutic strategy.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Mixed lineage leukemia (MLL/KMT2A) rearrangements (MLL-r) are common in acute myeloid leukemia (AML).
  • The role of Meningioma 1 (MN1), a HOXA9 and MEIS1 co-factor, in MLL-r leukemia is not fully understood.

Purpose of the Study:

  • To investigate the function of MN1 in MLL-r leukemia.
  • To determine if MN1 is a viable therapeutic target in MLL-r AML.

Main Methods:

  • CRISPR-Cas9 mediated deletion of MN1 in human and murine MLL-r leukemia models.
  • Analysis of cell cycle, proliferation, apoptosis, and differentiation.
  • Gene expression analysis and chromatin immunoprecipitation with sequencing (ChIP-seq).
  • siRNA-mediated knockdown of MN1 in primary MLL-r leukemia cells.

Main Results:

  • MN1 is essential for the in vivo leukemogenicity of MLL-r cells.
  • Loss of MN1 inhibits proliferation, induces apoptosis, and promotes differentiation.
  • MN1 maintains the active transcription of HOXA9, HOXA10, and their target genes (BCL2, MCL1, Survivin).
  • Anti-MN1 siRNA treatment reduces the clonogenic potential of MLL-r cells but not normal hematopoietic progenitors.

Conclusions:

  • MN1 plays a critical role in the pathogenesis of MLL-r leukemia.
  • MN1 is a promising therapeutic target for MLL-rearranged acute myeloid leukemia.

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