Philadelphia-like (Ph-like) B-cell precursor acute lymphoblastic leaukemia (B-ALL) is a high-risk subtype of leukaemia [1]. It is characterized by a gene expression profile similar to Philadelphia chromosome positive (Ph+) ALL, but lacking the BCR:: ABL1 rearrangement. Instead, Ph-like B-ALL represents a heterogeneous subtype driven by a diverse range of genetic aberrations and chromosomal rearrangements that converge on activated tyrosine kinase signalling [2, 3]. Integration of tyrosine kinase inhibitors into treatment regimens of Ph-like ALL patients has demonstrated early evidence of therapeutic efficacy, although results from larger clinical trials are pending [4].

Here we describe a novel PDGFRB lesion in a pediatric patient with Ph-like B-ALL. Unlike other PDGFRB fusions, this CD74:: PDGFRB variant does not form a chimeric protein, yet is constitutively active and sufficient to drive oncogenic transformation. We provide a model for a unique mechanism of kinase activation in Ph-like ALL which has implications for diagnostic fusion identification and provides key insights into kinase biology. The patient, a 22-month-old girl, presented with B-ALL and 86% blasts in the bone marrow (BM). Microarray analysis of the BM sample showed losses of chromosome regions 5q32 (partial PDGFRB and CD74), 7p12. 2 (46 kb, intragenic IKZF1 including exons 4 to 7), and 9p13. 3-p13. 1 (5Mb, including PAX5, sub-clonal~ 70%). The patient was stratified as high-risk and treated on the COG AALL1131 trial. At the end of induction, residual blasts of 46.3% were still detected. Given indications of a PDGFRB lesion, the patient received dasatinib in combination with consolidation chemotherapy, but despite a measurable response, maintained persistent minimal residual disease (0.396%) at the end of consolidation. The patient proceeded to receive a Kymriah CAR T infusion. Additional clinical details are provided in the Supplemental Materials section. We performed RNA-sequencing on the diagnostic sample. Gene expression analysis identified a Ph-like signature [5], and