Sara Palo- Institutionen för laboratoriemedicin

Title: Single cell and in vitro methods as a means to explore the fetal origin of infant ALL

Main supervisor: Charlotta Böiers

Reviewers: Marcus Järås and Björn Nilsson

Abstract

Background

Acute lymphoblastic leukemia (ALL) is one of the most common forms of childhood cancer. The initating mutation is known to often occur in utero, resulting in a pre-leukemic clone that after additional hits can develop into a leukemia. Differences in prognosis and commonly observed driver mutations compared to adult-onset ALL suggests that characteristics of the fetal hematopoietic landscape may play an important role.

Fetal hematopoiesis occurs in temporally overlapping waves in different niches, with the fetal liver (FL) functioning as an important hematopoietic organ from a few weeks post-conception until birth. Increased multilineage potential in myeloid/erythroid/megakaryocyte lineages has been shown in comparison to adult bone marrow (ABM), but less is known about the lymphoid/myeloid branching, which may be of importance considering the capacity of some forms of ALL to relapse as a lineage switched acute myeloid leukemia. 

Further knowledge of the fetal hematopoietic landscape and the effect of ALL driver mutations at this stage is needed to understand the initiation of childhood ALL. My PhD work includes single cell omics and in vitro studies to explore this topic.

Research

Performing cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on CD34+ hematopoietic stem and progenitor cells (HSPCs) from first trimester human FL, we observed a fetal-specific, potentially transient cell population. In addition, we could see an increased abundance of lymphoid progenitors and fewer transcriptionally defined HSCs than in ABM and a fetal gene signature which could separate some forms of ALL by age group. 

As a follow-up to this work, we have performed single cell Assay for Transposase-Accessible Chromatin (scATAC)-seq on HSPCs from the same developmental stage and are investigating fetal hematopoietic lineage priming and how lineage trajectories differ from adult counterparts. We found that fetal lymphoid and myeloid lineages appear to be less distinct than in ABM as well as differences in accessibility of enhancer regions associated with KMT2A-rearranged leukemia.

Additionally, we are using an in vitro, induced pluripotent stem cell (iPSC) based system to model fetal B lineage lymphopoiesis and the effect of leukemia-initiating mutations during this process. Preliminary results show that expression of the fusion gene KMT2A::AFF1, commonly observed in infants with B-lineage ALL, at the CD34+ stage of lymphopoiesis results in increased output of CD19+ cells. 

Published studies

Sommarin MNE, Olofzon R, Palo S, Dhapola P, Soneji S, Karlsson G, Böiers C. Single-cell multiomics of human fetal hematopoiesis define a developmental-specific population and a fetal signature. Blood Advances, 2023. https://doi.org/10.1182/bloodadvances.2023009808