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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Potentially important pharmacogenetics findings in Myeloid Blast Crisis Chronic myeloid neoplasms (MBC-CMN), using Integrated Genomic Sequencing

• Golnaz Ensieh Kazemi-Sefat,¹ Mohammad Keramatipour,² Saeed Talebi,³ Kaveh Kavousi,⁴ Mohammad Vaezi,⁵ Kazem Mousavizadeh,^6,*
  1. Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
  2. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  3. Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  4. Laboratory of Complex Biological Systems and Bioinformatics (CBB), Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
  5. Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  6. Department of Pharmacology, School of Medicine, Iran University of Medical Sciences Tehran, Iran
  
  
  
• Introduction: Chronic myeloid neoplasms (CMNs) are a group of disorders characterized by the overproduction of blood cells in the bone marrow, including red blood cells, white blood cells, and platelets. Chronic myeloid leukemia (CML) represents a well-studied model of leukemogenesis, though the molecular mechanisms driving progression to the blast crisis phase remain poorly understood. Primary myelofibrosis (PMF), another common CMN, can similarly progress to acute myeloid leukemia. Pharmacogenetics, the study of genetic factors influencing drug response, offers the potential to tailor treatment strategies for patients, especially those who are treatment-resistant or in advanced disease stages. This study focuses on identifying pharmacogenetically important variants in patients with myeloid blast crisis CMNs using integrated genomic sequencing approaches.
• Methods: Four patients with CMNs in myeloid blast crisis were included in this study: three with CML and one with PMF. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed on peripheral blood samples from the CML patients, while WES was conducted for the PMF patient and control samples. An in-house bioinformatics pipeline was used to evaluate cancer-related gene variants. The ACMG and AMP guidelines were applied to interpret potentially important findings (PIFs) and actionable pharmacogenetic findings (PAFs).
• Results: In three CML patients, 16 potentially important findings (PIFs) were identified across the five known classes of leukemogenic genes, including signaling pathway components (ABL1, PIK3CB, PTPN11), transcription factors (GATA2, PHF6, WT1, IKZF1), epigenetic regulators (ASXL1), tumor suppressor and DNA repair genes (BRCA2, ATM, CHEK2), and spliceosome components (PRPF8). In patient 4, seven PIFs were found, including variants in signaling pathways (JAK2-V617F, CSF3R-S624L), transcription factors (CTCF-R339Q), epigenetic regulators (IDH1-R132C), tumor suppressor and DNA repair genes (CHEK2-DS12), and spliceosome components (SRSF2-P95H, SF3B1-A149A). Notably, the CTCF-R339Q variant, which is typically found in solid tumors, was identified for the first time in a myeloid malignancy. Pharmacogenetically, key variants included ABL1-Y272H and ABL1-F359V in patients 1 and 2, respectively, leading to resistance to imatinib. Patient 3 did not have pathogenic pharmacogenetic variants but had several diagnostic and prognostic variants. In patient 4, the JAK2-V617F and IDH1-R132C variants were actionable, with responsiveness to Ruxolitinib and Ivosidenib, respectively. No pathogenic variants related to pharmacokinetics of standard CML drugs were found in any of the patients, and no Class 1 or 2 evidence was available for pharmacokinetically significant findings.
• Conclusion: Integrated genomic sequencing, particularly WES, offers significant potential to uncover pharmacogenetically important variants in myeloid blast crisis patients. These findings can be more comprehensive than custom NGS panels used in hematologic malignancies and may facilitate more personalized and targeted treatment strategies for patients with resistant or advanced disease. Additionally, these results contribute to the understanding of the molecular mechanisms driving blast phase development in CMNs, potentially improving patient outcomes through tailored therapies.
• Keywords: pharmacogenetics, Myeloid Blast Crisis, Chronic myeloid neoplasms, Integrated Genomic Sequencing