Abstract
The FLT3 Internal Tandem Duplication (FLT3ITD) 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 Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITD 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 Flt3ITD and Runx1 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 FLT3ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.
Highlights
Acute myeloid leukemia (AML) can occur at any stage of life yet the mutations that cause AML differ between childhood and adulthood, especially when one compares young children to adults (Chaudhury et al, 2015)
Flt3 was more highly expressed in HPCs than in HSCs at both ages (Figure 1A), consistent with prior studies (Buza-Vidas et al, 2011), but its expression did not change with age in either cell population (Figure 1A)
Since Flt3ITD has previously been shown to deplete adult HSCs (Chu et al, 2012), we tested whether the mutation has a similar effect on fetal HSC numbers
Summary
Acute myeloid leukemia (AML) can occur at any stage of life yet the mutations that cause AML differ between childhood and adulthood, especially when one compares young children to adults (Chaudhury et al, 2015). MLL translocations and GATA1 mutations are common in infant and early childhood AML but rare in adult AML (Andersson et al, 2015; Horton et al, 2013; Pine et al, 2007). Efforts to interpret AML genomes and translate the information into useful therapies will need to account for the influences of age and developmental context on leukemia cell biology. This will require a better understanding of how normal developmental programs shape the process of leukemogenesis
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