Infant BCP‐ALL (B Cell Precursor Acute Lymphoblastic Leukemia) patients harboring the fusion transcript MLL‐AF4 (t[4;11]) have a particularly poor prognosis and he summarized his laboratory's efforts to identify the cell of origin (COO).1, 2, 3 Taking a broad, multilayer omics approach, his findings have revealed the genetic and epigenetic evolution of a TCF3‐67 ZNF384/PTPN11‐driven clone in twins with BCP‐ALL, which supports the hypothesis that a pre‐VDJ primitive fetal hematopoietic progenitor or stem cell is the COO of TCF3‐ZNF384 and PTPN11 mutations. Here, TCF3 is linked to acute lymphoblastic leukemia.