IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia
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 dysre...
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2022
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oai:doaj.org-article:8339161c8984493e87427f6188e1cfae2021-11-26T04:26:40ZIKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia1936-523310.1016/j.tranon.2021.101291https://doaj.org/article/8339161c8984493e87427f6188e1cfae2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002825https://doaj.org/toc/1936-5233Cytokine 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.Ana Luiza Tardem MacielThayana da Conceição BarbosaCaroline Barbieri BlunckKarolyne WolchAmanda de Albuquerque Lopes MachadoElaine Sobral da CostaLavínia Lustosa BergierMárcia Trindade SchrammMaura Rosane Valério Ikoma-ColtutatoMecneide Mendes LinsThais Ferraz AguiarMarcela Braga MansurMariana EmerencianoElsevierarticleCRLF2, IKZF1, Gene expressionGene deletionsOutcomeB-ALLNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101291- (2022) |
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CRLF2, IKZF1, Gene expression Gene deletions Outcome B-ALL Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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CRLF2, IKZF1, Gene expression Gene deletions Outcome B-ALL Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Ana Luiza Tardem Maciel |
| title |
IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| title_short |
IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| title_full |
IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| title_fullStr |
IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| title_full_unstemmed |
IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia |
| title_sort |
ikzf1 deletions associate with crlf2 overexpression leading to a poor prognosis in b-cell precursor acute lymphoblastic leukaemia |
| publisher |
Elsevier |
| publishDate |
2022 |
| url |
https://doaj.org/article/8339161c8984493e87427f6188e1cfae |
| work_keys_str_mv |
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