1014 – AGE-DEPENDENT STEMNESS PROGRAMS THAT DRIVE PEDIATRIC ACUTE MYELOID LEUKEMIA

Pediatric acute myeloid leukemia is a genetically diverse malignancy with some mutations conveying particularly high risk for relapse and death. For example, NUP98-rearranged (NUP98r) AML occurs primarily in early to mid-childhood, and it carries an overall survival of only 10-30%. It is not clear why NUP98r AML occurs disproportionately in mid-childhood or how to more effectively treat it.

We used a combination of mouse and human models to identify self-renewal programs that sustain NUP98r AML and test whether they are engaged most efficiently during neonatal or juvenile stages of life, as might be expected based on peak age of presentation. We isolated a conserved leukemia stem cell (LSC) population. The LSC signature distinguishes NUP98r AML from other pediatric AML subtypes, and it includes new candidate targets for therapy.

Age greatly influences the capacity of pre-leukemic progenitors to self-renew, transform and give rise to LSCs. Specifically, we found that the fetal state confers an unanticipated layer of protection against NUP98r AML. NUP98::HOXA9 induction in fetal progenitors causes precocious erythroid differentiation. In contrast, NUP98::HOXA9 induction in postnatal progenitors hyperactivates self-renewal programs while preserving an otherwise normal hematopoietic differentiation trajectory. NUP98::HOXA9-expressing neonatal progenitors self-renew, form colonies and give rise to AML far more efficiently than fetal progenitors. The fetal state confers similar protection against KMT2A::MLLT1-driven AML, another high-risk subtype. Active fetal leukemia suppression may explain why fetal leukemias are exceedingly rare even when leukemogenic mutations arise before birth.

Interestingly, fetal protection does not extend to all pediatric AML oncoproteins. The infant AML driver, MNX1, causes marked expansion of fetal progenitors that dissipates almost entirely after birth. Thus, ontogeny has mutation-specific effects on self-renewal and leukemogenic potential.