Generating Tools to Investigate Infant Leukemia Disease Biology and Identify New Therapies Through Rapid Drug Screening.

Abstract

Infant Leukemia (IL) is a rare and aggressive congenital leukemia that is frequently caused by fusion genes involving lysine methyltransferase MLL (MLL1; KMT2A) and has a dismal prognosis. Further investigation into MLL-fusion disease biology and the role of contributing genetic factors, such as predisposing germline mutations to lysine methyltransferase KMT2C (MLL3), is needed. I genetically engineered two zebrafish models: a Cre/lox inducible transgenic model to express MLL-AF9 or MLL-ENL within specific blood cell lineages, and a knockout model of KMT2C homologs, kmt2ca and kmt2cb. I successfully established three blood cell specific CreERT2 expressing transgenic lines. However, MLL-AF9 and MLL-ENL transgenic fish failed to expression of the MLL-fusion genes and this model requires further development. Preliminary results indicate kmt2cb-/- larvae may have decreased myelopoiesis during primitive hematopoiesis suggesting a block in differentiation, while kmt2ca-/- fish have yet to be assessed. These models represent the development of new tools for IL research.