The Human Leukemic Oncogene MLL-AF4 Promotes Hyperplastic Growth of Hematopoietic Tissues in Larvae

Overview

Journal iScience

Publisher Cell Press

Date 2023 Sep 18

PMID 37720104

Authors

Julie A Johannessen

Miriam Formica

Aina Louise C Haukeland

Nora Rojahn Brathen

Amani Al Outa

Miriam Aarsund

Marc Therrien

Jorrit M Enserink

Helene Knaevelsrud

Affiliations

Soon will be listed here.

Abstract

-rearranged (-r) leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Here, we report a model system to explore the pathways affected in -r leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in the hematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion of orthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides an system to unravel the genetic interactors involved in leukemogenesis and offers a system for improved biological understanding of -r leukemia.

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