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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

CRISPR-Scan: Cas13a Mismatch Tolerance Enabled Ultra-Multiplexed Detection of Same-Site Indels in Acute Myeloid Leukemia.

  • Linlin Bai1
  • Bei Wang2
  • Mingmin Shi1
  • Dianwei Liu1
  • Huimin Ji1
  • Ting Wang3
  • Ziwei Wang4
  • Kaiming Guo1
  • Xinyang Dou1
  • Chunyan Qian1,5
  • Fang Zhang6,7
  • Yongming Wang1
2 more authors
  • Hongju Mao1
  • Rui Wang1,8
8 affiliations
  1. 1Center for Medical Research and Innovation, Department of Laboratory Medicine, Shanghai Pudong Hospital, Human Phenome Institute, State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China.
  2. 2State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, School of Medicine, Advanced Institute for Life and Health, Zhongda Hospital, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.
  3. 3Department of Hematology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
  4. 4Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, National Key Laboratory of Immunity and Inflammation, Changhai Hospital, Naval Medical University, Shanghai, China.
  5. 5Clinical Laboratory, Linping Campus, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  6. 6College of Biological Science and Engineering, Fuzhou University, Fuzhou, China.
  7. 7Research Institute for Microbiology and Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
  8. 8International Human Phenome Institutes, Shanghai, China.
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Abstract

Detection of gene mutations related to acute myeloid leukemia (AML) is crucial for its early diagnosis, personalized treatment, and recurrence monitoring. However, accurate detection of diverse mutations occurring at the same locus remains technically challenging. The CRISPR/Cas system, with its unique programmable nucleic acid recognition capabilities, provides a promising solution. Here, we elucidated that CRISPR/LwaCas13a is tolerant to consecutive substitutions but highly sensitive to insertions or deletions (indels) at specific positions of the spacer sequence, enabling rational CRISPR RNA (crRNA) design for multiplex detection of same-site indels. Guided by these principles, we achieved effective detection of ultra-multiplex nucleophosmin 1 (NPM1) c.863_864 4-bp insertions with a single crRNA, while maintaining specificity against the wild-type transcripts. We further established a one-pot CRISPR system, CRISPR-Scan, by integrating recombinase polymerase amplification with LwaCas13a cleavage. CRISPR-Scan enabled detection of mutations in backgrounds as low as 0.01%. In clinical validation, it identified NPM1 mutations in 43 of 120 AML patients, consistent with next-generation sequencing (NGS). Continuous monitoring of four AML patients indicated early recurrence with higher sensitivity than first-generation sequencing (FGS) and full concordance with NGS. A microfluidic chip and portable device further facilitate accurate AML mutation detection. This platform offers an efficient and convenient approach for early AML diagnosis and measurable residual disease (MRD) monitoring.

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Cite

BibTeXRIS
BibTeX
@article{bai2026crisprscan,
  title = {{CRISPR-Scan: Cas13a Mismatch Tolerance Enabled Ultra-Multiplexed Detection of Same-Site Indels in Acute Myeloid Leukemia.}},
  author = {Linlin Bai and Bei Wang and Mingmin Shi and Dianwei Liu and Huimin Ji and Ting Wang and Ziwei Wang and Kaiming Guo and Xinyang Dou and Chunyan Qian and Fang Zhang and Yongming Wang and Hongju Mao and Rui Wang},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78229},
  url = {https://europepmc.org/article/MED/42875730},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CRISPR-Scan: Cas13a Mismatch Tolerance Enabled Ultra-Multiplexed Detection of Same-Site Indels in Acute Myeloid Leukemia.
AU  - Linlin Bai
AU  - Bei Wang
AU  - Mingmin Shi
AU  - Dianwei Liu
AU  - Huimin Ji
AU  - Ting Wang
AU  - Ziwei Wang
AU  - Kaiming Guo
AU  - Xinyang Dou
AU  - Chunyan Qian
AU  - Fang Zhang
AU  - Yongming Wang
AU  - Hongju Mao
AU  - Rui Wang
PY  - 2026
DA  - 2026/10/14
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78229
UR  - https://europepmc.org/article/MED/42875730
AB  - Detection of gene mutations related to acute myeloid leukemia (AML) is crucial for its early diagnosis, personalized treatment, and recurrence monitoring. However, accurate detection of diverse mutations occurring at the same locus remains technically challenging. The CRISPR/Cas system, with its unique programmable nucleic acid recognition capabilities, provides a promising solution. Here, we elucidated that CRISPR/LwaCas13a is tolerant to consecutive substitutions but highly sensitive to insertions or deletions (indels) at specific positions of the spacer sequence, enabling rational CRISPR RNA (crRNA) design for multiplex detection of same-site indels. Guided by these principles, we achieved effective detection of ultra-multiplex nucleophosmin 1 (NPM1) c.863_864 4-bp insertions with a single crRNA, while maintaining specificity against the wild-type transcripts. We further established a one-pot CRISPR system, CRISPR-Scan, by integrating recombinase polymerase amplification with LwaCas13a cleavage. CRISPR-Scan enabled detection of mutations in backgrounds as low as 0.01%. In clinical validation, it identified NPM1 mutations in 43 of 120 AML patients, consistent with next-generation sequencing (NGS). Continuous monitoring of four AML patients indicated early recurrence with higher sensitivity than first-generation sequencing (FGS) and full concordance with NGS. A microfluidic chip and portable device further facilitate accurate AML mutation detection. This platform offers an efficient and convenient approach for early AML diagnosis and measurable residual disease (MRD) monitoring.
SN  - 2198-3844
ER  -