進行した慢性骨髄性白血病の遺伝的洞察

タイトル: Investigations on druggable gene mutations related to AML/ALL lineage genes in Advanced Phases of CML: Implications in patient-tailored therapy of blast crisis CML in TKI era

概要: Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP-CML) is treatable with overall survival equivalent to the general population. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-CML) and ultimately blast crisis (BC-CML), with the latter having an overall survival (OS) of 3-23 months, making it almost a fatal manifestation. Therefore, the treatment of BC-CML is one of the biggest challenges in modern cancer medicine. Moreover, the OS of BC-CML is very variable indicating its heterogeneity. Although BC-CML is a different clinical entity than acute leukemias, it resembles AML (as myeloid BC-CML) or ALL (lymphoid BC-CML). Therefore, this study was designed to find out AML-/ALL lineage gene mutations in BC-CML using very sensitive next-generation sequencing. Patients & Methods: The study included 141 CML patients (123 CP-CML as control groups; 6 AP-CML and 12 BC-CML as experimental groups). Most of the patients received imatinib mesylate (IM) as first-line treatment. All response criteria were per European LeukemiaNet (ELN) guidelines 2020. Whole exome sequencing (WES) was carried out to find out druggable gene mutations and the druggability of the mutated genes was determined using the online Artificial intelligence (AI) tool www.pandrugs.com. SAS/STAT software version 9.4 was used for data analysis (SAS Institute Inc., Cary, NC, USA). For statistical computing, the R package was employed (Vienna, Austria). The study was approved by the ethical committee of KAIMRC and carried out per the guidelines of the Helsinki Declaration Results: Overall male-to-female ratio was 1.6:1 and the mean age was 36.4 (range: 9 -67) years. Eighteen (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML finally. BC-ML patients had overall poorer response to TKIs and higher mortality rate (75%) that prompted to look for additional gene mutations. WES showed overall 64 AML-/ALL- associated gene mutated in advanced phase CML patients. Overall WES coverage was about 110X. AP-CML had 1644 variants, whereas BC-CML had 2531 variants, with a 54% gain in mutations from AP-CML to BC-CML (P< 0.000001). Among AML-/ALL- related mutated genes were NPM1 (%1.98), DNMT3A (%1.86), PML (%1.82), AKT1 (%1.62), CBL (%1.30), JAK2 (%0.71), TET2 (%0.59), IDH1 (%0.32), and BCL2. These mutations can be targeted by some drugs already approved by FDA to treat different blood cancers and include that included Venetoclax, Ivosidenib, Azacitidine, Decitabine, Doxorubicin, Vincristine, Quizartinib, Pacritinib, Vandetanib and Bortezomib. Conclusions: Our studies highlighted the role of myeloid-/lymphoid-lineage genetic abnormalities in CML blast crisis transformation and TKI-resistance. Whole-exome sequencing (WES)-based mutational analysis of BC-CML as experimental group and CP-CML as well as healthy subjects as controls found that genes exclusively mutated in BC-CML samples, in addition to BCR-ABL1, were RPTOR, BRCA1/2, STAB1, NF1, ACIN1, EGFR, NDRG2, ERG, MYH11, NPM1, DNMT3A, PML, AKT, CBL, JAK2, FLT-3, TET2, IDH1/2 and BCL2. Bioinformatics-based drug discovery (pandrugs2) analysis of WES data revealed various FDA-approved drugs targeting these blood cancer-related gene mutations detected in our BC-CM. It is important to mention that many of these drugs are already in clinical trials for BC-CML. . Hence we conclude that pan-cancer genetic analysis of BC-CML subjects by employing sensitive NGS assays coupled with AI-based drug discovery tools can detect druggable gene mutations in these patients that can provide rich sources of drug repurposing for personalized therapy of this fatal BC-CML. Keywords: Blast crisis Chronic Myeloid Leukemia; druggable mutations; pa-tient-tailored treatment; AML lineage genes; ALL lineage genes.