Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to <i>Flt3-</i>ITD mutations.

Abstract

The <i>FLT3</i> Internal Tandem Duplication (<i>FLT3^ITD</i>) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that <i>Flt3^ITD</i> and cooperating <i>Flt3^ITD/Runx1</i> mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3^ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3^ITD can activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions between <i>Flt3^ITD</i> and <i>Runx1</i> mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3^ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.