Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations

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.DOI: http://dx.doi.org/10.7554/eLife.18882.001

The efficiency of murine MLL-ENL–driven leukemia initiation changes with age and peaks during neonatal development

“…Lin28b is highly expressed in fetal HSCs and HPCs, but levels decline in neonatal progenitors, both in mice and humans. [32][33][34] To our surprise, sustained Lin28b expression suppressed rather than accelerated AML formation, suggesting that it may afford protection from MLL rearrangements during fetal stages before its expression declines in neonates. This may explain why, in humans, MLL rearrangements often occur prior to birth but overt leukemias do not usually arise until after birth.…”

“…Transplantations were performed as described previously. 32 All animals were housed in a pathogen-free barrier facility, and all procedures were performed according to an Institutional Animal Care and Use Committee-approved protocol.…”

“…Pten loss of function and Flt3internal tandem duplication mutations deplete hematopoietic stem cells (HSCs), expand committed progenitor populations, and cause leukemia only in juvenile or adult developmental contexts. 31,32 MLL rearrangements may have a similar propensity to cause leukemia in a fetal or neonatal context, particularly when they are expressed at physiologic rather than supraphysiologic levels.…”

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

“…Murine fetal progenitors have greater engraftment efficiency, biased lineage differentiation, and altered susceptibility to transformation compared with adult counterparts (24)(25)(26)(27). Analogous studies in humans showed that fetal and cord blood CD34 + cells are more proliferative and have a greater propensity to form myeloid colonies in methylcellulose culture than do adult cells (28,29).…”

Fetal hematopoietic stem cells are making waves

“…Altogether, this work suggested that Flk2 expression was associated with loss of self-renewal potential and initiation of robust proliferation in adult hematopoietic progenitors (10)(11)(12)14). During fetal hematopoiesis, however, activity of the FlkSwitch system correlated very differently with HSC phenotype and transplantability as compared to adult hematopoiesis, giving rise to the identification of the fetal drHSCs recently reported by Beaudin and coworkers (10 (16,17). Although transplantation assays have been instrumental to rigorously and prospectively define HSCs, findings by Beaudin and coworkers highlight the fact that transplantation into irradiated recipients remains an experimental assay, and that behavior of a given population of progenitors after transplantation (e.g., long-term reconstitution from drHSCs) does not necessarily match their in vivo activity (e.g., spontaneous disappearance of these cells in physiological conditions).…”