Heritable genetic background alters survival and phenotype of Mll-AF9-induced leukemias

Abstract

The MLL-AF9 fusion protein occurring as a result of t(9;11) translocation gives rise to pediatric and adult acute leukemias of distinct lineages, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and mixed-phenotype acute leukemia (MPAL). The mechanisms underlying how this same fusion protein results in diverse leukemia phenotypes among different individuals are not well understood. Given emerging evidence from genome-wide association studies that genetic risk factors contribute to MLL-rearranged leukemogenesis, here we tested the impact of genetic background on survival and phenotype of a well-characterized Mll-AF9 knockin mouse model. We crossed this model with five distinct inbred strains (129, A/J, C57BL/6, NOD, CAST) and tested their F1 hybrid progeny for dominant genetic effects on Mll-AF9 phenotypes. We discovered that genetic background altered peripheral blood composition, with Mll-AF9 CAST F1 having a significantly increased B-lymphocyte frequency, while the remainder of the strains exhibited myeloid-biased hematopoiesis, similar to the parental line. Genetic background also had an impact on overall survival, with Mll-AF9 A/J F1 and Mll-AF9 129 F1 having significantly shorter survival and Mll-AF9 CAST F1 having longer survival, compared with the parental line. Furthermore, we observed a range of hematologic malignancies, with Mll-AF9 A/J F1, Mll-AF9 129 F1, and Mll-AF9 B6 F1 developing exclusively myeloid cell malignancies (myeloproliferative disorder [MPD] and AML), whereas a subset of Mll-AF9 NOD F1 developed MPAL and Mll-AF9 CAST F1 developed ALL. This study provides a novel in vivo experimental model in which to evaluate the underlying mechanisms by which MLL-AF9 results in diverse leukemia phenotypes and provides definitive experimental evidence that genetic risk factors contribute to survival and phenotype of MLL-rearranged leukemogenesis.