Researcher in Clinical Medicine Director of the Cellular and Molecular Cytogenetics Laboratory at Ludaopei Medical Group Corresponding Author

Executive Dean of Beijing Ludaopei Hematology Research Institute, Chief of the Department of Pathology and Laboratory Medicine at Ludaopei Hospital.

Acute B lymphoblastic leukemia (B-ALL) is a clonal heterogeneous disease caused by mutations in genes associated with the development and proliferation of B lymphocytes, which obstructs the normal differentiation and maturation of B lymphocyte progenitor cells. Although the complete remission rate for adult ALL patients can exceed 80% after induction remission therapy, most patients eventually relapse, resulting in a low long-term survival rate. Recently, many new gene mutation types have been detected in relapsed B-ALL patients using technologies such as gene chips and second-generation sequencing. However, the exact pathogenesis of these gene mutations and their co-synergistic fusion genes in B-ALL remains unclear. At the recently concluded 28th European Hematology Association (EHA) annual meeting, a study (Abstract No: P346) by the team of Liu Hongxing and Wang Tong from Beijing Lu Daopei Hematology Institute was selected for this year’s EHA. The research aims to decode the structural changes of PAX5 and analyze other pathological fusion genes and gene mutations in B-ALL, while following up on the treatment and outcome of patients.

Research Results:

Among the 21 B-ALL patients, 11 (52.4%) had PAX5 structural variations. Of these, 5 were children (age <14 years) and 6 were adults, with a median age of 20 years (range 2.5-55 years); 9 were males and 2 were females, with a male-to-female ratio of 4.5:1. Five patients (45.4%) had fusion genes formed by translocation, with partner genes RNF38, BCL2, and NSD1 not previously reported in the literature. Four patients (36.3%) carried the PAX5::ZCCHC7 fusion gene, which was caused by a microdeletion of a 510Kb fragment on the short arm of chromosome 9, leading to abnormal PAX5 gene function. Two others (18.3%) carried an intragenic fragment deletion of the PAX5 gene (specifically exon6 and exon6-7, respectively). Out of these 11, 8 cases (72.7%) had mutations in the IKZF1 gene, with the IK10 gene being the most common (in 4 cases). Among these 11 cases, 8 had cytogenetic abnormalities that defined other B-ALL subtypes, including 2 with BCR::ABL1, 3 with BCR::ABL1-like (specifically NUP214::ABL1, EBF1::PDGFRB, and RCSD1::ABL2), 1 with E2A::PBX1, 1 with ETV6::RUNX1, and 1 with hyperdiploid. Two were CRLF2@IGH positive, but without any genetic abnormalities that define B-ALL subtypes. Of the 6 high-risk patients, 5 underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T therapy. These 5 patients remained in remission until the last follow-up (21-63 months). Those who did not undergo allo-HSCT died of relapse 13 months after onset.

Researcher’s  Remarks – Professor Wang Tong:

The PAX5 gene plays a crucial role in maintaining the development of normal B lymphocytes. Its abnormalities play a key role in the occurrence and differentiation of B-ALL, serving as one of the driving factors. The structural variations of the PAX5 gene are diverse and heterogeneous. Current detection methods are challenging to recognize fully. The potential pathogenic mechanism remains unclear, requiring further research and exploration. OGM offers unique advantages in accurately analyzing genomic structural variations and copy number abnormalities, providing a new methodological choice. Through OGM and RNA-seq analysis of 21 initial, relapsed, or refractory B-ALL patients, we identified several partner genes of PAX5, of which three partner genes have not been reported in the literature. Further research is needed to track the pathogenic mechanisms of different partner genes and their impact on treatment. We also found that PAX5 abnormalities occur more frequently in BCR::ABL1-positive and BCR::ABL1-like patients, providing an important direction for further research on the pathogenesis of these two subtypes.