Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3+-mediated leukemic phenotype

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Abstract
Mutations, which activate Fms-like-tyrosinkinase 3 (FLT3) are frequent occurrences in acute myeloid leukemia. Two distinct types of mutations have been described: internal duplication of the juxtamembranous domain (ITD) and point mutations of the tyrosine kinase domain (TKD). Although both mutations lead to constitutive FLT3 signaling, only FLT3-ITD strongly activates Signal Transducer and Activator of Transcription (STAT5). In a murine transplantation model, FLT3-ITD induces a myeloproliferative neoplasm, while FLT3-TKD leads to a lymphoid malignancy with significantly longer latency. Here we report that the presence of STAT5 is critical for the development of a myeloproliferative disease by FLT3-ITD in mice. Deletion of Stat5 in FLT3-ITD-induced leukemogenesis leads not only to a significantly longer survival (96 days vs 10 days) of the diseased mice but also to an immunophenotype-switch with expansion of the lymphoid cell compartment. Interestingly, we were able to show differential STAT5 activation in FLT3-ITD+ myeloid and lymphoid murine progenitors. STAT5 target genes such as Oncostatin M were highly expressed in FLT3-ITD+ myeloid but not in FLT3-ITD+ lymphoid progenitor cells. Strikingly, FLT3-TKD expression in combination with Oncostatin M is sufficient to reverse the phenotype to a myeloproliferative disease in FLT3-TKD mice. Thus, lineage-specific STAT5 activation in hematopoietic progenitor cells predicts the FLT3+-mediated leukemic phenotype in mice.

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