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

  • Lorenz Bastian (Geteilte/r Erstautor/in)
  • Thomas Beder (Geteilte/r Erstautor/in)
  • Malwine Jeanette Barz (Geteilte/r Erstautor/in)
  • Sonja Bendig
  • Lorenz Bartsch
  • Wencke Walter
  • Nadine Wolgast
  • Björn Brändl
  • Christian Rohrandt
  • Björn-Thore Hansen
  • Alina M Hartmann
  • Katharina Iben
  • Dennis Das Gupta
  • Miriam Denker
  • Johannes Zimmermann
  • Michael Wittig
  • Guranda Chitadze
  • Martin Neumann
  • Folker Schneller
  • Walter Fiedler
  • Björn Steffen
  • Matthias Stelljes
  • Christoph Faul
  • Stefan Schwartz
  • Franz-Josef Müller
  • Gunnar Cario
  • Lana Harder
  • Claudia Haferlach
  • Heike Pfeifer
  • Nicola Gökbuget
  • Monika Brüggemann
  • Claudia D Baldus

Beteiligte Einrichtungen

Abstract

Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .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 German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0006-4971
DOIs
StatusVeröffentlicht - 04.04.2024

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Copyright © 2023 American Society of Hematology.

PubMed 38153913