Abstract

Infant leukemias arise as either B cell acute lymphoblastic leukemia (B-ALL) or acute myeloid leukemia (AML) and are primarily driven by MLL/KMT2A-rearrangements (MLLr). Prior work has shown that MLLr transform fetal/neonatal hematopoietic progenitors more efficiently than adult progenitors. However, the genetics and epidemiology of MLLr leukemias present an important paradox. MLLr arise during late gestation under conditions that would seemingly favor leukemic transformation (i.e., fetal/neonatal progenitors have high proliferation rates and self-renewal). Furthermore, MLLr infant leukemias require very few cooperating mutations for transformation. Yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal stages of life. Here, we use mouse models to show that fetal expression of MLL::ENL (also called KMT2A::MLLT1) creates a heritable, leukemia-resistant state that persists after birth and even after transplantation. When MLL::ENL is induced shortly after birth, transformation proceeds efficiently in this context. Heritable, fetal protection against leukemic transformation potentially explains the low incidence of congenital leukemias in humans, and it illustrates how ontogeny not only conveys leukemia-permissive states, but also leukemia resistant states. Furthermore, we show that MLL::ENL promotes a B cell bias in fetal/neonatal progenitors, even though the mouse models ultimately develop AML. We identified SKIDA1 as a temporally-restricted effector of this B cell bias, suggesting a potential explanation for why infant MLLr leukemias most often present as B-ALL, whereas non-infant MLLr leukemias more often present as AML. This work provides a better understanding of how leukemogenic mutations and normal developmental programs interact. If we can understand how ontological programs repress or potentiate leukemogenesis, we can potentially reprogram progenitors to treat high-risk pediatric leukemias.

Committee Chair

Jeffrey Magee

Committee Members

Daniel Link; Jeffrey Bednarski; Jorge Di Paola; Laura Schuettpelz

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-9558-152X

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