Understanding of the onset and recurrence pattern of intractable acute lymphocytic leukemia based on clone analysis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08723
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: Sanada Masashi 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 高度診断研究部長 (20529044)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 急性リンパ性白血病 / 微小残存病変 / クローン構造 / 乳児白血病 / KMT2A転座

Outline of Final Research Achievements

In this study, we performed target-capture sequencing to identify clonal IGH-VDJ rearrangements and genomic breakpoints of MLL (KMT2A) rearrangements. We quantified these clone sizes by droplet-digital PCR to elucidate detailed clonal structures in ALL cases with MLL rearrangement.
In the KMT2A::AFF1 or KMT2A::MLLT1 cases, multiple IGH-DJ rearrangements were identified, and most cases were composed of various minor clones in cells with KMT2A rearrangement. On the other hand, ALL cases with MLL rearrangement to other genes have a limited number of rearrangements and were composed of simple monoclonal structures. Oligoclonal IGH rearrangements were also identified in infant ALL cases without KMT2A rearrangements, but most of the rearrangements were complete V(D)J type. KMT2A::AFF1 and MLLT1 cases were often difficult to evaluate minimal residual disease using IGH rearrangements, and MRD evaluation using genomic KMT2A breakpoints was considered useful alternative.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

乳児ALLがoligoclonalな再構成を有していることは既に知られていたが、本解析により単に再構成の数では表せないクローン構造を正確に示すことができた。KMT2A転座例において転座切断点を用いたMRD評価の有用性は次期臨床試験において前向きに検証予定であるが、転座相手遺伝子によって、その重要性は異なることが明らかとなった。クローン構造の理解に基づく正確なMRD評価は、再発リスク評価による治療成績の改善や新規治療開発の治療判定に寄与するとともに、不必要な造血幹細胞移植やCART療法を回避することの臨床的、医療経済的な意義は非常に大きいと考える。