TEL/PDGFβR Tyrosine Kinase Fusion Specifically Activates Myeloid Differentiation Programs, and Converts Lymphoid Progenitors into the Myeloid Lineage.

Acute leukemias are classified into myeloid and lymphoid subtypes according to their phenotypic characteristics. Leukemic cells, however, sometimes co-express myeloid and lymphoid phenotypes, or switch their phenotype from myeloid to lymphoid lineages and vice versa. The conventional classification of leukemias is based mainly upon the concept that leukemic phenotype reflects a progenitor stage at which leukemic transformation occurs, or that it represents a stage at which transformed hematopoietic stem cells (HSCs) become incapable of further differentiation. Here we propose another possibility that phenotype of leukemias could be determined by instructive signals from the leukemic transformation mechanism itself. We found that TEL/PDGFβR (T/P), a tyrosine kinase fusion isolated from chronic myelomonocytic leukemia, can instruct myeloid lineage commitment and conversion at stem and progenitor stages of hematopoiesis. The T/P gene was transduced into purified progenitors or HSCs by using a retrovirus carrying a green fluorescent protein reporter. HSCs transduced with T/P (T/P+ HSCs) spontaneously formed GM colonies without cytokines. Furthermore, T/P+ HSCs were incapable of differentiation into B cells on OP9 stromal layer in the presence of IL-7. To test the effect of T/P on lymphoid commitment more precisely, we transduced T/P into purified common lymphoid progenitors (CLPs) that normally differentiate only into T, B and NK lineages. In a limiting dilution assay, 1 in 7 control-GFP transduced CLPs generated B cell progeny in vitro, while only 1 in 500 T/P+ CLPs differentiated into B cells. Instead, surprisingly, the majority of T/P+ CLPs and even T/P+ thymic proT cells quickly differentiated into granulocytes and monocytes in vitro. We then transplanted T/P+ CLPs into lethally irradiated congenic mice. T/P+ CLPs again differentiated into Gr-1+ granulocytes and monocytes in vivo. Gene expression analyses showed that T/P+ CLPs upregulated GM-related molecules including C/EBPα and GM-CSFRα immediately after T/P transduction, while transduction of either C/EBPα or GM-CSFRα also reprogrammed CLPs into the myeloid lineage as we reported previously. Thus, T/P signaling can activate these critical GM-related molecules in lymphoid progenitors to convert them into the myeloid lineage. These data collectively suggest that at least some types of oncogenic tyrosine kinase fusions can specify leukemic phenotypes, through activating critical signals for lineage commitment.