A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1

Abstract

SummaryETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19−IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19−IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state.

High sensitivity and clonal stability of the genomic fusion as single marker for response monitoring in ETV6‐RUNX1‐positive acute lymphoblastic leukemia

“…We have not observed persistence of ETV6‐RUNX1 fusion at low levels, which might represent the preleukemic clone and therefore result in false‐positive MRD results . Moreover, it is not known whether the preleukemic clone would be detectable during polychemotherapy and the preleukemic clone could additionally already have clonal D‐J IG heavy chain rearrangements …”

“…47 Moreover, it is not known whether the preleukemic clone would be detectable during polychemotherapy and the preleukemic clone could additionally already have clonal D-J IG heavy chain rearrangements. 48 The clonal homogeneity and intrinsic oncogenic role of the translocation might be particularly instrumental for MRD interpretation after stem cell transplantation, when massive regeneration of normal lymphoid progenitors might lead to low levels of nonspecific amplification or false-positive oligoclonal proliferation. 49 We did not expect to discover major divergence using ETV6-RUNX1 fusion sites in our cohort, well monitored by several Ig/TCR rearrangements in parallel.…”

“…MRD reduction kinetics is plotted from the time of relapse diagnosis, through maintenance therapy, and before/after hematopoietic stem cell transplantation. In patients with an isolated extramedullary relapse(48)(49)(50)(51)(52), the submicroscopic level of bone marrow infiltration at diagnosis is depicted. MRD results measured by ETV6-RUNX1 fusions are shown MRD assessment during frontline and relapse treatment were compared.…”

Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

“…However, there is another possible way of interpreting the specific relationship between LMO2 and T‐ALL, and it is to consider that the LMO2 oncogene is directly capable of imposing the phenotypic characteristics of the tumor in a non‐T target cell. In fact, Rag‐1 expression has been detected in early progenitors in both mice and humans (Boiers et al , , ), therefore providing a mechanistic possibility for translocations to happen at very early hematopoietic developmental stages. If this second option is true, and LMO2 can indeed impose a T‐cell program in a non‐T target cell, it would be difficult, however, to prove this fact in human tumors, since the deconvolution of the sequential events in the evolution of the leukemia becomes almost impossible due to the clonal and sub‐clonal accumulation of genetic alterations by the time of the clinical presentation of the full‐blown T‐ALL.…”

“…However, there is another possible way of interpreting the specific relationship between LMO2 and T-ALL, and it is to consider that the LMO2 oncogene is directly capable of imposing the phenotypic characteristics of the tumor in a non-T target cell. In fact, Rag-1 expression has been detected in early progenitors in both mice and humans (Boiers et al, 2013(Boiers et al, , 2018, therefore providing a mechanistic possibility for translocations to happen at very early hematopoietic developmental stages. If this second option is true, and LMO2 can indeed impose a T-cell progenitors is not relevant per se (Ruggero et al, 2016).…”