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Macaraeg, J.

Publications and source records attributed to Macaraeg, J..

2 recordsLinked to original sources

Genetic analysis of C. elegans Haspin-like genes shows that hasp-1 plays multiple roles in the germline

Haspin is a histone kinase that promotes error-free chromosome segregation by recruiting the Chromosomal Passenger Complex (CPC) to mitotic and meiotic chromosomes. Haspin remains less well studied than other M-phase kinases and the models explaining Haspin function have been developed primarily in mitotic cells. Here, we generate new mutations in the C. elegans Haspin homologs hasp-1 and hasp-2 and characterize their phenotypes. We show that hasp-1 is responsible for all predicted functions of Haspin and that loss of function of hasp-1 using classical and conditional alleles produces defects in germline stem cell proliferation, spermatogenesis, and confirms its role in oocyte meiosis. Genetic analysis suggests hasp-1 acts downstream of the Polo-like kinase plk-2 and shows synthetic interactions between hasp-1 and two genes expected to promote recruitment of the CPC by a parallel pathway that depends on the kinase Bub1. This work adds to the growing understanding of Haspin function by characterizing a variety of roles in an intact animal. Summary statementWe characterize new mutations in the C. elegans homologs of the histone kinase Haspin and show roles in spermatogenesis, germline proliferation and genetic interactions during oocyte meiosis.

genetics↗

Dual Targeting of FLT3 and LSD1 Disrupts the MYC Super-Enhancer Complex in Acute Myeloid Leukemia

Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood super-enhancer, suppressing super-enhancer activation as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies provide preclinical rationale for the investigation of dual FLT3/LSD1 inhibition in a clinical trial.

cancer biology↗