Whole exome sequencing detected CTCF R339Q variant along with IDH1 R132C, SRSF2 P95H in myeloid blast crisis of a JAK2 V617F positive chronic myeloid neoplasm (primary myelofibrosis): a case report

Background: Primary Myelofibrosis (PMF) is the most common Chronic Myeloid Neoplasm (CMN) that eventually transforms into acute myeloid leukemia. The underlying molecular mechanisms in the blastic phase remain largely unexplored. Using whole exome sequencing, several unusual clinically significant variants were detected in a blast phase PMF (PMF-BP) patient. Case Presentation: A 59-year male, previously known as JAK2 V617F positive, BCR-ABL1 negative PMF case, was admitted with fever, pneumonia, pancytopenia, and 30% blast in the peripheral blood. Bone marrow aspiration and immunophenotyping confirmed blast crisis PMF (PMF-BP). AMP and ACMG guidelines were used to interpret potentially important findings (PIFs) and potentially actionable findings (PAFs). Seven PIFs entail various functional classes of cancer genes, including signaling pathway components (JAK2-V617F, CSF3R-S624L), transcription factors (CTCF-R339Q), epigenetic regulators (IDH1-R132C), tumor suppressor and DNA repair genes (CHEK2-D311N), and components of the spliceosome (SRSF2-P95H, SF3B1-A149A). JAK2-V617F, IDH1-R132C, CTCF-R339Q, and SRSF2-P95H variants were known cancer biomarkers in this patient and were characterized as actionable findings. Although the discovered variant in CTCF (p.R339Q) was initially documented in solid tumors, it has not been previously reported in myeloid malignancies. Conclusion: Genomic sequencing, combined with logical filtering methods, can aid in identifying medically actionable findings that may improve PMF-BP personalized management. Additionally, this study may expand the landscape of blastic transformation variants in CMNs and provide additional insight into its genetic background. Keywords: blast phase, PAF, PIF, Primary Myelofibrosis, Whole-exome sequencing