Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements.

Vasiliki Symeonidou,Hélène Jakobczyk,Salem Bashanfer,Richard A Anderson,Rishi S Kotecha,Camille Malouf,Foteini Fotopoulou,Andrew J Finch,Katrin Ottersbach

doi:10.1016/j.celrep.2021.109900

Abstract

SummaryInfant MLL-AF4-driven acute lymphoblastic leukemia (ALL) is a devastating disease with dismal prognosis. A lack of understanding of the unique biology of this disease, particularly its prenatal origin, has hindered improvement of survival. We perform multiple RNA sequencing experiments on fetal, neonatal, and adult hematopoietic stem and progenitor cells from human and mouse. This allows definition of a conserved fetal transcriptional signature characterized by a prominent proliferative and oncogenic nature that persists in infant ALL blasts. From this signature, we identify a number of genes in functional validation studies that are critical for survival of MLL-AF4+ ALL cells. Of particular interest are PLK1 because of the readily available inhibitor and ELOVL1, which highlights altered fatty acid metabolism as a feature of infant ALL. We identify which aspects of the disease are residues of its fetal origin and potential disease vulnerabilities.

Highlights

Infant MLL-AF4-driven pro-B acute lymphoblastic leukemia (ALL) is the most common leukemia in infants (Bonaventure et al, 2017; Meyer et al, 2018)
The fetal transcriptome is characterized by a proliferative and oncogenic nature Infant MLL-AF4+ ALL arises in utero; we speculated that studying differences between fetal and neonatal tissues would allow us to understand how the unique origin of this disease affects its phenotype
We identified 2,394 differentially expressed (DE) genes between the two populations, with 1,162 more highly expressed in fetal liver (FL) cells (Table S1, tab 1)

Summary

Introduction

Infant MLL-AF4-driven pro-B acute lymphoblastic leukemia (ALL) is the most common leukemia in infants (Bonaventure et al, 2017; Meyer et al, 2018) It arises in utero and is an aggressive disease with a dismal prognosis (Ford et al, 1993; Meyer et al, 2018; Pieters et al, 2019; Sanjuan-Pla et al, 2015). It has been shown that the t(4;11) translocation is the only molecular abnormality identified in the majority of patients (Agraz-Doblas et al, 2019; Andersson et al, 2015) This clean mutational landscape suggests that the complexity of this disease is attributable to the fusion protein and the fetal origin of the leukemia-initiating cell. It has proven difficult to develop faithful disease models (Ottersbach et al, 2018), indicating that, for identification of specific therapeutic targets, a better understanding of the biology of the disease is required

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