LIN28B supports fetal B-cell development and KMT2A::AFF1 leukemia initiation

Researchers compared transcriptomes of human fetal and adult hematopoietic stem and progenitor cells, identifying LIN28B and its downstream effectors as part of a fetal-specific gene signature also found in infant acute lymphoblastic leukemia (iALL). Functional assays in human fetal liver CD34+ cells showed that LIN28B supported proliferation and stem-like properties, as well as B-cell and natural killer cell development. The team then used a CRISPR-based human fetal liver cell model to study KMT2A::AFF1 translocation.

Without LIN28B, the engineered fetal cells did not transform after induction of the translocation. LIN28B-expressing leukemias proliferated more in vitro and in vivo, and this advantage was lost when LIN28B was knocked down. Mechanistic analyses linked LIN28B to stabilization of early B-lymphoid genes, epigenetic regulators, and cell-cycle and antiapoptotic genes. These findings support a role for fetal-cell biology in KMT2A::AFF1 leukemia initiation, but they come from cellular and model-system experiments, not clinical testing. The authors identify LIN28B as a potential target in LIN28B-expressing leukemia; the study does not establish a treatment or clinical benefit.