Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development

Abstract

Several lines of evidence suggest that childhood leukemia, the most common cancer in young age, originates during in utero development. However, our knowledge of the cellular origin of this large and heterogeneous group of malignancies is still incomplete. The identification and characterization of their cell of origin is of crucial importance in order to define the processes that initiate and sustain disease progression, to refine faithful animal models and to identify novel therapeutic approaches. During embryogenesis, hematopoiesis takes place at different anatomical sites in sequential waves, and occurs in both a hematopoietic stem cell (HSC)-dependent and a HSC-independent fashion. Despite the recently described relevance and complexity of HSC-independent hematopoiesis, few studies have so far investigated its potential involvement in leukemogenesis. Here, we review the current knowledge on prenatal origin of leukemias in the context of recent insights in developmental hematopoiesis.

Generation of a H9 Clonal Cell Line With Inducible Expression of NUP98-KDM5A Fusion Gene in the AAVS1 Safe Harbor Locus

“…Increasing evidence support that most pediatric leukemias originate by the acquisition of driving genetic alterations before birth ( Greaves et al, 2003 ; Cazzola et al, 2021 ). However, it is unknown the developmental stage and identity of the cell(s) in which the genetic hit occurs ( Cazzola et al, 2021 ; Lopez et al, 2019 ).…”

“…Increasing evidence support that most pediatric leukemias originate by the acquisition of driving genetic alterations before birth ( Greaves et al, 2003 ; Cazzola et al, 2021 ). However, it is unknown the developmental stage and identity of the cell(s) in which the genetic hit occurs ( Cazzola et al, 2021 ; Lopez et al, 2019 ). Thus, we decided to induce the expression of NK5A during the hematopoietic differentiation of the H9 iNK5A clonal lines using the STEMdiff™ Hematopoietic Kit (Stem Cell Technologies) ( Figure 2A ).…”

“…Acute Myeloid Leukemia (AML) contributes to 20% of acute leukemia cases in children and, although the overall survival has improved over the past years, still around 50% of the pediatric patients will experience relapse ( de Rooij et al, 2015 ; AplencMeshinchi et al, 2020 ). Pediatric AML is a heterogeneous group of blood disorders characterized by different genetic abnormalities that are frequently originated during embryonic development in a still unknown cell type(s) ( Cazzola et al, 2020 ).…”

Variant to function mapping at single-cell resolution through network propagation

“…Given existing controversies on the cell of origin for B-cell ALL 45,46 , the most common form of this disease comprising approximately 80% of childhood ALL cases, we focused on assessing the dynamic differentiation process of B cells to explore enrichments across this trajectory. We established a trajectory of B cell development as a continuum from HSCs and progenitors to mature B cells and plasma cells 28,47 (Fig.…”

The EHA Research Roadmap: Normal Hematopoiesis

“…Even though many leukemic events occur after birth, several hematological diseases were shown to take place during pregnancy and are accounting for 30% of childhood and adolescent cancers. 44 Understanding the initial mutation events triggering leukemia and modelling the initiation and progression of the disease will be of prime importance for the future. Access to human samples and manipulation of human pluripotent stem cells will certainly be a key issue.…”