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Maciel ALT, Barbosa TDC, Blunck CB, et al. IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia. Transl Oncol. 2021;15(1):101291doi: 10.1016/j.tranon.2021.101291.
Maciel, A. L. T., Barbosa, T. D. C., Blunck, C. B., Wolch, K., Machado, A. A. L., da Costa, E. S., Bergier, L. L., Schramm, M. T., Ikoma-Coltutato, M. R. V., Lins, M. M., Aguiar, T. F., Mansur, M. B., & Emerenciano, M. (2021). IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia. Translational oncology, 15(1), 101291. https://doi.org/10.1016/j.tranon.2021.101291
Maciel, Ana Luiza Tardem, et al. "IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia." Translational oncology vol. 15,1 (2021): 101291. doi: https://doi.org/10.1016/j.tranon.2021.101291
Maciel ALT, Barbosa TDC, Blunck CB, Wolch K, Machado AAL, da Costa ES, Bergier LL, Schramm MT, Ikoma-Coltutato MRV, Lins MM, Aguiar TF, Mansur MB, Emerenciano M. IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia. Transl Oncol. 2021 Nov 23;15(1):101291. doi: 10.1016/j.tranon.2021.101291. Epub 2021 Nov 23. PMID: 34826720.
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Transl Oncol. 2021 Nov 23;15(1):101291. doi: 10.1016/j.tranon.2021.101291. Epub 2021 Nov 23.

IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia.

Translational oncology

Ana Luiza Tardem Maciel, Thayana da Conceição Barbosa, Caroline Barbieri Blunck, Karolyne Wolch, Amanda de Albuquerque Lopes Machado, Elaine Sobral da Costa, Lavínia Lustosa Bergier, Márcia Trindade Schramm, Maura Rosane Valério Ikoma-Coltutato, Mecneide Mendes Lins, Thais Ferraz Aguiar, Marcela Braga Mansur, Mariana Emerenciano

Affiliations

  1. Acute Leukemia RioSearch Group, Division of Clinical Research and Technological Development, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro, RJ, 20231050, Brazil.
  2. Department of Paediatrics, Instituto de Puericultura e Pediatria Martagão Gesteira, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  3. Onco-Haematology Section, Prontobaby Hospital da Criança Ltda, Rio de Janeiro, Brazil.
  4. Onco-Haematology Section, Prontobaby Hospital da Criança Ltda, Rio de Janeiro, Brazil; Haematology Unit, Hospital do Câncer I, Instituto Nacional de Câncer - INCA, Rio de Janeiro, Brazil.
  5. Flow Cytometry Laboratory, Amaral Carvalho Foundation, Jaú, SP, Brazil; Sabin Medicina Diagnóstica, Federal District, Brasília, Brazil.
  6. Paediatric Oncology Unit, Instituto de Medicina Integral Prof Fernando Figueira, Recife, PE, Brazil.
  7. Acute Leukemia RioSearch Group, Division of Clinical Research and Technological Development, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro, RJ, 20231050, Brazil; Onco-Haematology Section, Instituto Estadual de Hematologia Arthur Siqueira Cavalcanti, Rio de Janeiro, Brazil.
  8. Acute Leukemia RioSearch Group, Division of Clinical Research and Technological Development, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro, RJ, 20231050, Brazil; Department of Paediatrics, Children's Hospital, John Radcliffe Hospital and MRC Weatherall Institute of Molecular Medicine - WIMM, University of Oxford, Oxford, UK. Electronic address: [email protected].
  9. Acute Leukemia RioSearch Group, Division of Clinical Research and Technological Development, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro, RJ, 20231050, Brazil. Electronic address: [email protected].

PMID: 34826720 DOI: 10.1016/j.tranon.2021.101291

Abstract

Cytokine Receptor-Like Factor 2 (CRLF2) overexpression occurs in 5-15% of B-cell precursor acute lymphoblastic leukaemia (B-ALL). In ∼50% of these cases, the mechanisms underlying this dysregulation are unknown. IKAROS Family Zinc Finger 1 (IKZF1) is a possible candidate to play a role in this dysregulation since it binds to the CRLF2 promoter region and suppresses its expression. We hypothesised that IKZF1 loss of function, caused by deletions or its short isoforms expression, could be associated with CRLF2 overexpression in B-ALL. A total of 131 paediatric and adult patients and 7 B-ALL cell lines were analysed to investigate the presence of IKZF1 deletions and its splicing isoforms expression levels, the presence of CRLF2 rearrangements or mutations, CRLF2 expression and JAK2 mutations. Overall survival analyses were performed according to the CRLF2 and IKZF1 subgroups. Our analyses showed that 25.2% of patients exhibited CRLF2 overexpression (CRLF2-high). CRLF2-high was associated with the presence of IKZF1 deletions (IKZF1del, p = 0.001), particularly with those resulting in dominant-negative isoforms (p = 0.006). Moreover, CRLF2 expression was higher in paediatric samples with high loads of the short isoform IK4 (p = 0.011). It was also associated with the occurrence of the IKZF1 plus subgroup (p = 0.004). Furthermore, patients with CRLF2-high/IKZF1del had a poorer prognosis in the RELLA05 protocol (p = 0.067, 36.1 months, 95%CI 0.0-85.9) and adult cohort (p = 0.094, 29.7 months, 95%CI 11.8-47.5). In this study, we show that IKZF1 status is associated with CRLF2-high and dismal outcomes in B-ALL patients regardless of age.

Copyright © 2021. Published by Elsevier Inc.

Keywords: B-ALL; CRLF2, IKZF1, Gene expression; Gene deletions; Outcome

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