Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL

Abstract

Distinct diagnostic entities within BCR::ABL1-positive ALL are currently defined (ICC): 'lymphoid-only', with BCR::ABL1 observed exclusively in lymphatic precursors versus 'multilineage', where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of n=327 BCR::ABL1-positive ALL patients (age: 2 years - 84 years, median: 46) and identified two main gene expression clusters reproducible across four independent patient cohorts. FISH analysis of FACS-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n=18/18 vs n=3/16 patients, p<0.001), indicating that a 'multilineage' or 'lymphoid' BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A / PAX5 deletions / hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current GMALL protocols resulted in comparable disease-free survival (DFS) for 'multilineage' vs. 'lymphoid' cluster patients (3-year DFS: 70% vs 61%, p=0.530; n=91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.

Mutation and cell state compatibility is required and targetable in Ph+acute lymphoblastic leukemia minimal residual disease

“…5 Previous studies have identified developmental heterogeneity across ALL, 6,7 as well as in Ph+ ALL specifically. 8,9 This developmental heterogeneity has also been linked to treatment response for multiple classes of inhibitors. 6,7,10 Recent work specifically in Ph+ ALL examined developmental subtypes that align with earlier (Early-Pro) and later developmental (Late-Pro) B cell features, finding that the former was associated with poor overall survival upon treatment with the first-generation TKI imatinib.…”

“…8 Commitment to earlier or later stages of development has been associated with cooperating alterations in lineage-defining transcription factors ( EBF1 deletion or deletions in IKZF1, PAX5, and CDKN2A, respectively), suggesting that developmental state adherence – and its associated therapeutic response – may be mutationally driven and static upon leukemic transformation. 8,9 However, other studies have nominated the potential for a leukemia’s dominant developmental states to shift in response to therapeutic pressure. Illustratively, non-mutational mechanisms of chemotherapy resistance have been observed in ALL patient-derived xenografts (PDXs), whereby leukemia cells transiently adopt a dormant, stem-like state at MRD; 11 others have demonstrated post-treatment shifts in the abundance of dormant subpopulations mimicking earlier developmental stages.…”