Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases

Abstract

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in timespace clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches.

Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

“…This is only possible if the oncogenic event(s) have an inherent reprogramming capacity and the leukemia-initiating cell has the necessary plasticity (Sanchez-Garcia, 2015). Several prior studies have been involved in studying aberrations in HSC/PC as an important driver for myeloid and Bcell hematopoietic neoplasms through a reprogramming mechanism (Perez-Caro et al, 2009;Vicente-Duenas et al, 2012a,c;Green et al, 2014;Rodriguez-Hernandez et al, 2017), but to our knowledge, there is no evidence that a similar mechanism may be relevant for T-ALL. Two alternative explanations can be contemplated to interpret the close association existing between the LMO2 oncogene and human T-ALL development: on the one side, the classical interpretation that considers that the role of LMO2 as the T-ALL-initiating genetic alteration takes place in a committed/differentiated target T cell.…”

Insights into the prenatal origin of childhood acute lymphoblastic leukemia

“…Additional alterations to this hypothesis have been made, including delayed infection [22] and population mixing [23]. Recent studies have provided in vivo evidence by linking ALL in Pax5-heterozygous mice [24] and ETV6-RUNX1 + mice [25] to exposure to infection. The exact mechanisms of leukemic transformation through infection are not yet fully understood, but dysregulation of the immune system may play a major role.…”

“…Furthermore, the mixing of populations has been postulated as a causal factor for leukemic transformation [23]. Recent studies have shown that exposure to infection can trigger the progression from preleukemia to ALL [24,25]. A dysregulated immune response by activation of preleukemic B cells through memory T helper cells [26] and inactivity of NK cells have also been discussed [27][28][29].…”

Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening

“…Also, the frequency of preleukemic cells in healthy blood or cord blood was controversially discussed, ranging from ,10 25 to 10 23 . [21][22][23][24][25] Asterisks mark the breakpoint present in the REH cell line. The breakpoints identified in the present study are indicated by orange (N424), blue (N726), red (N817), green (N823), and yellow (N890) arrows.…”