Abstract
Infant acute myeloid leukemia (AML) is a heterogeneous disease, genetically distinct from
its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially
common in affected infants of less than 1 year of age, and are associated with a dismal prognosis.
While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively
identified. This knowledge could lead to a better understanding of the biology of the disease and
support the identification of new therapeutic vulnerabilities. Over the last few years, important
progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have
highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis,
which is instead largely sustained by HSC-independent progenitors. Here, we used conditional CreLox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic
hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for
Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in
HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not
when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement
in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation
of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSCindependent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced
leukemic transformation, and can likely act as cells of origin of infant AML.
its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially
common in affected infants of less than 1 year of age, and are associated with a dismal prognosis.
While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively
identified. This knowledge could lead to a better understanding of the biology of the disease and
support the identification of new therapeutic vulnerabilities. Over the last few years, important
progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have
highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis,
which is instead largely sustained by HSC-independent progenitors. Here, we used conditional CreLox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic
hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for
Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in
HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not
when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement
in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation
of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSCindependent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced
leukemic transformation, and can likely act as cells of origin of infant AML.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 3624 |
| Tidsskrift | Cancers |
| Vol/bind | 15 |
| Udgave nummer | 14 |
| Antal sider | 19 |
| ISSN | 2072-6694 |
| DOI | |
| Status | Udgivet - 2023 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:This study was supported by research grants from Fondazione Cariplo (Biomedical Research Conducted by Young Researchers, ID: 2018-0102) and the Leukemia Research Foundation (New Investigator Blood Cancer Research Grant Program, ID: 831382) to E.A.
Publisher Copyright:
© 2023 by the authors.