Poster Presentation 35th Lorne Cancer Conference 2023

Unusual PDGFRB fusion reveals novel mechanism of kinase activation in Ph-like ALL. (#169)

Fatimah B. Jalud 1 , Hansen J. Kosasih 2 , Lauren M. Brown 3 4 , Lachlan McAloney 1 , Chris R. Horne 5 6 , Nadia Davidson 1 6 7 , Louise E. A. Ludlow 2 , Alicia Oshlack 1 8 9 , Seong L. Khaw 2 10 , James M. Murphy 5 6 , Paul G. Ekert 1 3 4 8 , Teresa Sadras 1 8
  1. Peter MacCallum Cancer Center, Melbourne, VICTORIA, Australia
  2. Murdoch Children's Research Institute, Melbourne, Victoria, Australia
  3. University of New South Wales Centre for Childhood Cancer Research, Sydney, New South Wales, Australia
  4. Children's Cancer Institute, Lowy Cancer Research Centre, Sydney, New South Wales, Australia
  5. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  6. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  7. School of Biosciences, University of Melbourne, Melbourne, Victoria, Australia
  8. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  9. School of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia
  10. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia

Ph-like acute lymphoblastic leukemia is a high-risk subtype of leukemia that is driven by a range of genetic aberrations and chromosomal arrangements. In this subtype, chimeric fusion proteins are significant drivers of constitutive kinase activation. We report a novel fusion between CD74 and PDGFRB in a pediatric patient with B-ALL. The patient had high residual blasts following induction chemotherapy, consistent with induction failure. Given the indication of a PDGFRB lesion, the patient proceeded to receive dasatinib in conjunction with consolidation therapy as a curative bridge to a CAR T cell infusion. Sequence analysis of the CD74::PDGFRB fusion revealed an unusual structure with no clear in-frame transcript arising from exon 1 of CD74. Molecular dissection exposed a non-canonical in-frame ATG start codon within PDGFRB that drives expression of a truncated PDGFRB protein. Structural modelling revealed that the juxtamembrane domain in the full-length PDGFRB receptor acts as an autoinhibitory loop, this interaction is disrupted in the truncated PDGFRB protein allowing constitutive auto-activation of the kinase. Consistent with this, we show that unlike full-length PDGFRB, expression of CD74::PDGFRB is sufficient to drive downstream signaling and cell transformation in B cell models. This study highlights a new mechanism of kinase activation in Ph-like ALL, wherein the aberrant expression of a ‘loose’ kinase domain is sufficient to drive auto-activation and leukemic transformation. This encourages a closer inspection of putative leukemia drivers which may be overlooked following out-of-frame sequence predictions.