Clonal origins of ETV6-RUNX1+ acute lymphoblastic leukemia: studies in monozygotic twins

Abstract

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.

Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia

“…The frequency of such cells may be low and precise identification would require the analysis of much greater amounts of primary patient material than was obtainable. The cell of origin of B-ALL has previously been considered to be a lymphoid-restricted cell but has more recently been postulated to be a multipotent progenitor, as suggested for ETV6-RUNX1- positive ALL from studies of monozygotic twins (Alpar et al, 2015), our study supports this conclusion. Sequencing of the genomic breakpoints of the EPOR rearrangements provided compelling evidence that the alterations arise from RAG-mediated recombination, and gene expression profiling demonstrates RAG expression in mouse and human progenitor cell populations, supporting acquisition of the EPOR rearrangement in a hematopoietic progenitor that then acquires additional alterations such as deletion of the CDKN2A/B tumor suppressor loci that contribute to the establishment of the leukemic clone.…”

Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia

“…Models of development from preleukemia to overt-leukemia have been established in ETV6-RUNX1 and hyperdiploid-ALL by comparing leukemia that occurred in monozygotic twins, or backtracking studies of archived neonatal blood samples (44,45). In this model, the initiating ETV6-RUNX1 fusion or hyperdiploidy abnormality was often acquired in utero to generate a preleukemic founder clone, the latter subsequently acquired a series of CNAs/SNVs, and eventually transformed to overt/frank ALL.…”

Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

“…However, the cell of origin in which the initial functional impact of the fusion gene occurs has been contentious. It may lie anywhere antecedent to B precursor cells in the lineage hierarchy [57]. IgH, TCR and ETV6/RUNX1 are leukemia-specific molecular markers in E/R -positive ALL.…”

“…However, studies on clonal IgH and/or TCR gene rearrangements in E/R -positive ALL have demonstrated that the fetal cell type in which clonal advantage is elicited by E/R can be propagated after B-lineage commitment [25, 57, 66]. Consistent with this conclusion, retroviral transduction of the E/R fusion gene in murine and human models suggested that E/R could promote self-renewal of early B-cell precursors [25, 66].…”

“…Recently, a study analyzed all varieties of Ig and TCR gene rearrangements in five pairs of monozygotic twins concordant for ALL. They proved that the E/R fusion initially expanded in an early B-cell lineage-committed progenitor, most likely at the pro-B, or possibly at the pre-B, cell stage [57]. The effect of E/R at the pre-B or pro-B cell stage is intriguing, as it may prove that the E/R fusion gene can directly influence the phenotype of leukemic cells.…”