AMKL chimeric transcription factors are potent inducers of leukemia

Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathologic including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI, and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2 which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain of function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor (MEP) gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathologic drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies. To gain insight into the genetic etiology of AMKL patients without Down syndrome, we previously performed transcriptome sequencing on diagnostic blasts from a discovery cohort of 14 pediatric cases and substantiated our findings in a recurrency/validation cohort. This analysis confirmed the unique biology of this disease as evidenced by novel fusion transcripts including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI1, and NIPBL-HOXB9. To confirm their role in oncogenesis and gain insight into the mechanism whereby these novel fusions promote disease, we introduced each of them as well as their individual gene counterparts into murine hematopoietic progenitor cells that were assessed in murine syngeneic transplantation models. Accompanying histologic, immunophenotypic, and genome-wide molecular characterization of resultant tumors delineated common and unique modes of leukemogenesis.