Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Abstract

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specifi c associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2 , are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and singlecell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2 -induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE:This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

“…These data demonstrated striking features of infant AML: (i) fusion genes are able to induce AML transformation without additional cooperation, (ii) there is a paucity of associated mutations and (iii) gene expression profile clusters in defined groups [4,5,29].…”

“…To understand the mechanistic role of these different molecular lesions, mouse models have been developed using gene editing to create transgenic mice. In parallel, patients derived samples have been used to generate xenotransplants in immunocompromised mice (PDX) [5][6][7]. These transgenic mice have helped understanding the role of the different fusions in leukemic transformation.…”

“…They have also shown the paucity of mutations compared to adult AML [3,4]. Further, they have interrogated the molecular specificities of this subgroup, modeling different genetic fusions in mice [5,6]. They have been able to show the role of ontogeny and fetal hematopoiesis development in the emergence of infant AML.…”

“…During fetal life hematopoiesis, the fetal liver supports self-renewal and differentiation of hematopoietic stem cells and multipotent progenitors (HSC/MPPs). Oncogenic events, mainly fusions, occurring in these fetal liver progenitors impact leukemia phenotype [5,7]. How these fusions impact transcription, disrupt transcription factor balance and promote leukemogenesis may reveal opportunities for treatment.…”

“…How these fusions impact transcription, disrupt transcription factor balance and promote leukemogenesis may reveal opportunities for treatment. Thus, targeted approaches could interfere with oncogenic determinants to improve treatment efficiency of infant leukemia often characterized by very poor outcome [5,7].…”