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Background <p>Screening for BCR-ABL1 kinase domain (KD) mutations is routinely implemented in cases of treatment failure for chronic myeloid leukaemia and Philadelphia-positive acute lymphoblastic leukaemia. However, timely deciphering their clonal relationship via mutation profiling that requires identification of mutation types, quantification of mutant abundance, and differentiation between compound and polyclonal mutations (CMs and PMs), remains difficult during therapy.</p> Methods <p>Herein, we established a protocol that identified mutation types and further distinguished clonal relationships by combining mini-sequencing of MeltArray with allele segregation of droplet digital PCR (ddPCR).</p> Results <p>The analysis showed that 78 samples (18.93%) were mutant, of which 50 (64.1%) harboured single mutations, and 28 (35.9%) contained multiple mutations, including double-, triple-, quadruple- and hepta-mutants. These results agreed with NGS, except one sample with F317L and L324Q mutations, where L324Q was beyond MeltArray’s scope. Among cases containing multiple mutations, 85.71% were PMs, 10.71% were CMs, and 3.57% were mixed CMs and PMs. Retrospective analysis revealed that clonal relationships in BCR-ABL1 KD mutations were highly dynamic during therapy.</p> Conclusions <p>The MeltArray-ddPCR protocol enables dynamic profiling of BCR-ABL1 KD mutations to determine clonal status, improving prediction of drug susceptibility and leukaemia outcomes.</p> <p></p>

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Innovative rapid screening for complex BCR-ABL1 kinase domain mutations in TKI-treated leukaemia patients

  • 期刊论文

  • 发表日期：

    2025年6月30日

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  • Yanping Lan,
  • Jun Deng,
  • Pujing He,
  • Wen Huang,
  • Anqi Zhu,
  • Xiaoxia Guo,
  • Lv Xiong,
  • Qiuying Huang,
  • Yu Hu,
  • Qingge Li

摘要

Background

Screening for BCR-ABL1 kinase domain (KD) mutations is routinely implemented in cases of treatment failure for chronic myeloid leukaemia and Philadelphia-positive acute lymphoblastic leukaemia. However, timely deciphering their clonal relationship via mutation profiling that requires identification of mutation types, quantification of mutant abundance, and differentiation between compound and polyclonal mutations (CMs and PMs), remains difficult during therapy.

Methods

Herein, we established a protocol that identified mutation types and further distinguished clonal relationships by combining mini-sequencing of MeltArray with allele segregation of droplet digital PCR (ddPCR).

Results

The analysis showed that 78 samples (18.93%) were mutant, of which 50 (64.1%) harboured single mutations, and 28 (35.9%) contained multiple mutations, including double-, triple-, quadruple- and hepta-mutants. These results agreed with NGS, except one sample with F317L and L324Q mutations, where L324Q was beyond MeltArray’s scope. Among cases containing multiple mutations, 85.71% were PMs, 10.71% were CMs, and 3.57% were mixed CMs and PMs. Retrospective analysis revealed that clonal relationships in BCR-ABL1 KD mutations were highly dynamic during therapy.

Conclusions

The MeltArray-ddPCR protocol enables dynamic profiling of BCR-ABL1 KD mutations to determine clonal status, improving prediction of drug susceptibility and leukaemia outcomes.