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ACUTE LYMPHOBLASTIC LEUKEMIA

The recombinome of IKZF1 deletions in B-cell precursor ALL

Leukemia volume 37, pages 1727–1731 (2023)Cite this article

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The occurrence of IKZF1 deletions increases the risk of relapse in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [1, 2]. Therefore, the development of methods for their rapid and accurate detection is clinically relevant. Traditionally, the identification of IKZF1 deletions has been based on multiplex ligation-dependent probe amplification (MLPA), although distinct approaches are also available, including array-based methods, optical gene mapping, and whole genome sequencing. The latter techniques provide a broad panorama of copy number or structural alterations, but demand validation or their high costs limit the application in routine diagnosis worldwide. Multiplex (M)-PCR is a feasible and accurate complementary method for the screening and validation of the majority of IKZF1 deletions, specially recurrent intragenic ones: Δ2–3, Δ2–7, Δ2–8, Δ4–7, Δ4–8 [3, 4]. In addition, several studies describe the occurrence of non-recurrent IKZF1 deletions in BCP-ALL, and proved their importance for determining patient outcome [5]. Therefore, here we performed an international effort to include a large cohort of BCP-ALL samples, and review the literature to provide the landscape of IKZF1 deletions in this subtype of leukemia. Our study presents a special focus on non-recurrent deletions, illustrating their genetic profile, impact on patient outcome, and providing the basis for upgrading current methods to determine IKZF1 status. In addition, we analyze sequence features underlying different types of IKZF1 deletions to explore possible mechanisms of leukemogenesis.

To determine whether non-recurrent IKZF1 deletions also impact patient outcome, we performed Kaplan–Meier analysis comparing their survival (n = 18) to matched patients with IKZF1 wild-type (n = 36) or ∆4–7 (n = 36). Patient and clinical information of these comparative groups are detailed in Table S5. The three IKZF1 status groups had similar OS rates (P = 0.60 by log-rank test; Fig. 1d). On the other hand, the 5-year CIR differed between those groups (P = 0.057 by Gray test; Fig. 1e), especially between IKZF1 ∆4–7 and wild-type (14.7% vs. 37.7%; P = 0.027). Of note, the 10-year CIR was still 14.7% in patients without IKZF1 deletion, but reached 44.6% and 50.1% in the groups with ∆4–7 and non-recurrent deletion, respectively. Although the first studies addressing the relationship between IKZF1 deletions and BCP-ALL prognosis had more representation of common deletions (i.e., Δ4–7 and Δ1–8), it was also demonstrated that less frequent deletions (i.e., Δ2–7 and Δ2–8) reduces event-free survival [5]. In this regard, our study adds novel information to previous results, especially for IKZF1 exon 1 deletions. In summary, we have substantial evidence that IKZF1 deletions confer a dismal prognosis for BCP-ALL patients, regardless of the deletion range. Therefore, the identification of these alterations might contribute to appropriate risk stratification and therapeutic benefits for these patients.

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Fig. 1: Genetic landscape of IKZF1 deletions and its impact on BCP-ALL outcome.
Fig. 2: Breakpoint map and genetic signatures of IKZF1 deletions.

Data availability

All data supporting the findings of this study are available from the corresponding author upon reasonable request. The TARGET dataset is available at the Genomic Data Commons (GDC) Data Portal (https://portal.gdc.cancer.gov/projects).

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Acknowledgements

We are grateful to the children and their parents for their participation in research. We also thank Australian and New Zealand Children’s Haematology and Oncology Group hospital staff and oncologists and Sydney Children’s Tumor Bank Network for their support and the MRD teams in Sydney and Monza. We thank Dr. Jinghui Zhang, Dr. Xiaotu Ma, Dr. Qingsong Gao, and Dr. Charles Mullighan for kindly providing contig sequences of IKZF1 deletions. We also appreciate the contributions made by Luana Batista as well as the technical assistance provided by Alessandra J. Faro, André F. Duarte, and Jodie Giles. These results were partially based on data derived from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET; https://ocg.cancer.gov/programs/target) initiative.

Funding

BAL was supported by the Brazilian Ministry of Health and INCA. BAL received a return research grant (Ref 3.2 - 1193718 - BRA - HFSTCAPES-P) and a fellowship for a short stay in Germany (Ref 3.2 - BRA / 1193718) from the Alexander von Humboldt Foundation. ME is supported by Brazilian National Council of Technological and Scientific Development – CNPq (PQ-311220/2020-7) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ (E_26/203.214/2017; E-26-010.101072-2018; and E-26/010.002187//2019) research grants. RM was supported by grants from the DFG (Ma 1876/12-1) and Wilhelm Sander foundation (2018.070.2). RS, LDP and BD received research grant funding from NH&MRC Australia APP1128727 and Cancer Australia PdCCRS APP1024232.

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Authors and Affiliations

  1. Program of Molecular Carcinogenesis and Division of Clinical Research, Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA), Rio de Janeiro, Brazil

    Bruno A. Lopes, Heloysa Bouzada, Ana Luiza Tardem Maciel, Thayana C. Barbosa, Caroline P. Poubel, Caroline Barbieri & Mariana Emerenciano

  2. DCAL, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany

    Bruno A. Lopes, Claus Meyer, Marius Külp, Patrizia Larghero & Rolf Marschalek

  3. Molecular Diagnostics, Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia

    Nicola C. Venn & Rosemary Sutton

  4. Cancer Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW, Australia

    Luciano Dalla Pozza

  5. Sydney Children’s Hospital, Randwick, NSW, Australia

    Draga Barbaric

  6. Tettamanti Cente, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

    Chiara Palmi, Grazia Fazio, Claudia Saitta & Gianni Cazzaniga

  7. Arthur Siqueira Cavalcanti Hematology Institute (HEMORIO), Rio de Janeiro, Brazil

    Thais F. Aguiar

  8. Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil

    Mecneide M. Lins

  9. Hospital Amaral Carvalho, São Paulo, Brazil

    Maura R. V. Ikoma-Colturato

  10. Prontobaby Hospital da Criança, Rio de Janeiro, Brazil

    Marcia Schramm

  11. Serviço de Hematologia, Hospital do Câncer I, INCA, Rio de Janeiro, Brazil

    Marcia Schramm

  12. Hospital Israelita Albert Einstein, São Paulo, Brazil

    Eduardo Chapchap

  13. Medical Genetics, School of Medicine and Surgery, University of Milan Bicocca, Monza, Italy

    Gianni Cazzaniga

Authors
  1. Bruno A. Lopes
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  2. Claus Meyer
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  24. Mariana Emerenciano
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Contributions

BAL, CM and ME designed the study. ALTM, TCB, CPP, CB, NCV, RS, CP, GF, CS, and GC contributed with MLPA data of individual patients. LDP, DB, CP, GF, TFA, MML, MRVIC, MS, EC, GC, and RS provided samples and patient data. BAL and ALTM performed MLPA validation of suspicious rare deletions. BAL and ME provided these materials. RM, CM, and BAL provided materials for NGS sequencing. BAL, MK, and PL performed library preparation and NGS sequencing. PL mapped these data. HB carried out M-PCR. BAL prepared data, reviewed literature, performed data analyses and wrote the manuscript. ME reviewed the first draft of the manuscript and provided important insights to this work. All authors critically reviewed and approved the final version of the manuscript.

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Correspondence to Bruno A. Lopes or Mariana Emerenciano.

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Lopes, B.A., Meyer, C., Bouzada, H. et al. The recombinome of IKZF1 deletions in B-cell precursor ALL. Leukemia 37, 1727–1731 (2023). https://doi.org/10.1038/s41375-023-01935-8

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