MEIS1 overexpression

The BH3 mimetic venetoclax, in combination with low dose cytarabine, decitabine or azacitidine has shown clinical efficacy in newly diagnosed acute myeloid leukemia (AML) (1, 2). We also demonstrate that neutrophils can be recovered using IL-3 neutralisation in combination with venetoclax in AML engrafted mice. Taken together, these findings provide biologic insight for IL-3 inhibition alongside venetoclax to reduce the incidence of cytopenias observed in elderly AML patients.

Moreover, the dihydroorotate dehydrogenase (DHODH) inhibitor that reduces leukaemogenesis in mammals effectively restored haematopoiesis in Tg(drl:hoxa9;hsp70:meis1) embryos and improved their late survival. Thus, Tg(drl:hoxa9;hsp70:meis1) zebrafish is a rapid-onset high-penetrance AML-like disease model, which provides a novel tool to harness the unique advantages of zebrafish for mechanistic studies and drug screening against HOXA9/MEIS1 overexpressed high-risk AML.

Finally, we demonstrate that HoxA9 and Meis1 proteins are stabilized by post-translational modification. Mutation of HoxA9/Meis1 phosphorylation sites or inhibition of casein kinase 2 lead to rapid protein degradation suggesting a potential pathway for pharmacological intervention.

SMC4 is higher expressed in haploinsufficient and NPM1c positive AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared to AML cells with non-mutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.

In this review article, the molecular mechanism of the oncological role of the MEIS1 protein in leukemia and LSC is discussed. In addition, it was suggested that MEIS1 protein could be utilized as a possible treatment target in leukemia with an emphasis on the inhibition of MEIS1, which is overexpressed in LSC.

Cmpd 41 also demonstrated superior in vivo anti-leukemic activity in multiple AML xenograft models as monotherapy and demonstrated synergy with a hypomethylating agent, decitabine in TP53 mutated AML...In summary, we introduce a best in class DHODH inhibitor with a data-driven combination strategy for both AML and MM. Our studies suggest a highly synergistic combination strategy involving immunotherapy for AML and other hematologic malignancies.

Taken together, higenamine could be employed as a starting point for the development of more selective and potent LSD1 inhibitors. Our work firstly reveals the non-classical epigenetic regulation mechanism of higenamine in cancers, and also demonstrates the efficacy of higenamine for MLL-rearranged leukemia therapy.

Moreover, an in vivo experiment confirmed the inhibitory role of silenced ELF1 in tumor growth, with a decreased level of MEIS1 and GFI1. Taken together, our study elucidated a potential mechanism that ELF1 promoted cell progression by increasing GFI1 and METS1 as well as decreasing FBW7 expression in glioma.

The current case formed part of the KMT2A-rearranged acute lymphoblastic leukemia cluster in a T-distributed stochastic neighbor embedding plot. The aggressive clinical course and RNA-sequencing results of the present case suggest that KMT2A-rearranged DLBCL shares biological features with KMT2A-rearranged leukemia.