Title: Inducing MLL-AF4 in different hematopoietic stem and progenitor cells to study the initiation of childhood B cell leukemia

Main supervisor: Charlotta Böiers

Reviewers: Anna Hagström and Daniel Bexell

Abstract

Background

Leukemia is a cancer of early blood-forming cells. There are several types of leukemia, which are divided based on whether the leukemia is acute (fast-growing) or chronic (slow-growing), and whether it starts in myeloid cells or lymphoid cells. Among acute leukemia, B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent in children. B-ALL of infancy, occurring at <1 year of age, is a unique entity where the majority of cases are frequently triggered by chromosomal translocations involving the MLL gene. The most frequent MLL translocation in infants is MLL-AF4, associated with unfavorable prognosis and increased risk of relapse.

One of the major challenges to study this type of leukemia has been the in-utero origin of the disease, making it difficult to recapitulate in murine models. This has led to multiple studies and hypothesis about the cell of origin of MLL-AF4 B-cell leukemia, but it still remains unknown. My PhD research focus on understanding how MLL-AF4 leukemia initiates in infants and investigating the role that MLL-AF4 has in different cell populations. This can provide more information about the unique features of the disease that will help to develop new target therapies for childhood leukemia.

Research

To model the pre-leukemic state a Tet-off mouse model combined with a Cre-LoxP was generated, in which MLL-AF4 targets different cell populations in utero across the hematopoietic hierarchy. In this project Hematopoietic stem and progenitor cells (HSPCs), lympho-myeloid progenitors and ProB cells were selected. The selection was based on MLL-AF4 giving rise to a B cell leukemia leading us to hypothesize that the B cell path is the one being more susceptible to the mutation.

Our results have shown that when MLL-AF4 was induced to HSPCs at the embryonic stage a significant increase of Pre-ProB progenitors was observed. In addition, MLL-AF4 confers to the Pre-ProB cells the ability to produce not only B cells but also myeloid cells. This is relevant due to oftentimes (~30%) MLL-AF4 giving rise to myeloid leukemias after relapse, indicating that the leukemia initiating cell could have the potential to give rise to both B cells and myeloid cells. In addition, our preliminary results showed that when MLL-AF4 was induced to HSPCs postnatally the expanded Pre-ProB population was not present, suggesting that there are some key differences in how MLL-AF4 affects fetal and adult cells respectively.

Published studies

Fatemeh Safi, Parashar Dhapola, Eva Erlandsson, Linda Geironson Ulfsson, Ariana S. Calderón, Charlotta Böiers, Göran Karlsson. In vitro clonal multilineage differentiation of distinct murine hematopoietic progenitor populations. STAR Protocols. https://doi.org/10.1016/j.xpro.2022.101965