MANIPULATING CELL STATES FOR LEUKAEMIA DIFFERENTIATION THERAPY USING NETWORK PHARMACOLOGY

Acute myeloid leukaemia (AML) is a rapidly fatal blood cancer which is characterized by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. In this proof-of-concept study, we demonstrate a novel utility of the MOGRIFY® algorithm in identifying combinations of transcription factors (TFs) and drugs which induce granulocytic differentiation of the NB4 acute promyelocytic leukaemia (APL) cell line. Connectivity Map (CMAP) analysis of these TFs and their target networks identified dimaprit and mebendazole as a drug combination which induces myeloid differentiation. Alternatively, we show that genetic and pharmacologic manipulation of MOGRIFY-identified TFs, specifically MYC and IRF1, also leads to co-operative induction of differentiation in APL cells. We also outline potential mechanisms by which MYC down-regulates IRF1 expression in NB4 cells. We anticipate that MOGRIFY could be used to discover TF-based differentiation therapies for other subtypes of leukaemia or cancers.

Author dc:creator

• LEE LIN MING

• Leukaemia, differentiation, pharmacology, transcription, drugs, cancer