IGH Rearrangement Evolution in Adult KMT2A-rearranged B-cell Precursor ALL: Implications for Cell-of-origin and MRD Monitoring

B lymphoid neoplasms originate from a single malignantly transformed immune cell, whose immunoglobulin heavy chain (IGH) rearrangement profile is carried by the entire expanded malignant population and mirrors its differentiation status. However, in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and depending on the developmental stage of malignant transformation, multiple new but related IGH rearrangements may result from RAG-mediated recombination that may still be active in the malignant clone. Moreover, such phenomena complicate the identification of molecular minimal residual disease (MRD) markers and have implications for MRD monitoring. Therefore, deep analysis of IGH gene rearrangement patterns and clonal evolution mechanisms—ongoing recombination of incomplete DJH rearrangements (VH-DJH) and at a later stage also VH replacement (VH-rep), known as receptor editing in physiological B-cell development—may allow new insights into the stage of B-cell differentiation arrest of the leukemia-driving subpopulation that ultimately determines the outcome (Figure 1A), and provide more accurate MRD results.

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