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. 2018 May 25;9(40):25971-25982.
doi: 10.18632/oncotarget.25411.

Surface expression of Cytokine Receptor-Like Factor 2 increases risk of relapse in pediatric acute lymphoblastic leukemia patients harboring IKZF1 deletions

Agata Pastorczak #  1 , Lukasz Sedek #  2 , Marcin Braun  1   3   4 , Joanna Madzio  1   3 , Alicja Sonsala  2 , Magdalena Twardoch  2 , Wojciech Fendler  1   5 , Karin Nebral  6 , Joanna Taha  1 , Marta Bielska  1 , Patryk Gorniak  7 , Magdalena Romiszewska  8 , Michal Matysiak  8 , Katarzyna Derwich  9 , Monika Lejman  10 , Jerzy Kowalczyk  10 , Wanda Badowska  11 , Maciej Niedzwiecki  12 , Bernarda Kazanowska  13 , Katarzyna Muszynska-Roslan  14 , Grazyna Sobol-Milejska  15 , Grazyna Karolczyk  16 , Andrzej Koltan  17 , Tomasz Ociepa  18 , Tomasz Szczepanski  2 , Wojciech Młynarski  1
Affiliations

Surface expression of Cytokine Receptor-Like Factor 2 increases risk of relapse in pediatric acute lymphoblastic leukemia patients harboring IKZF1 deletions

Agata Pastorczak et al. Oncotarget. .

Abstract

We prospectively examined whether surface expression of Cytokine Receptor-Like Factor 2 (CRLF2) on leukemic blasts is associated with survival and induction treatment response in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Flow cytometric analysis of bone marrow-derived leukemia cells revealed that 7.51% (29/286) of 386 pediatric BCP-ALL patients were CRLF2-positive (CRLF2pos) at diagnosis. The median minimal residual disease (MRD) was lower in CRLF2pos than CRLF2-negative (CRLF2neg) patients on day 15 (MRD15) after induction therapy [0.01% (0.001-0.42%) vs. 0.45% (0.05-3.50%); p=0.001]. By contrast, the MRD15 was higher in Ikaros family Zinc Finger Protein 1 (IKZF1)-deleted BCP-ALL patients than in BCP-ALL patients without IKZF1 deletions [1.18% (0.06-12.0%) vs 0.33% (0.03-2.6%); p=0.003]. Subgroup analysis showed that MRD15 levels were lower in IKZF1Δ/CRLF2pos patients than in IKZF1Δ/CRLF2neg patients [0.1% (0.02-5.06%) vs. 2.9% (0.25-12%); p=0.005]. Furthermore, MRD15 levels were higher in IKZF1WT/CRLF2neg patients than in IKZF1WT/CRLF2pos patients [0.40% (0.04-2.7%) vs. 0.001% (0.001-0.01%)]. Despite the low MRD15 levels, IKZF1Δ/CRLF2pos patients showed poorer relapse-free survival (RFS) than other patient groups (p=0.003). These findings demonstrate that surface CRLF2 expression is associated with increased risk of relapse in pediatric BCP-ALL patients harboring IKZF1 deletions.

Keywords: acute lymphoblastic leukemia; gene; minimal residual disease; relapse.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Flowchart shows selection strategy and classification of pediatric BCP-ALL patients at diagnosis and at days 15 and 33 of the treatment
Figure 2
Figure 2. Flow cytometry profiles showing different CRLF2 expression patterns on leukemic blasts in the pediatric BCP-ALL patients
Representative FACS plots showing surface CRLF2 staining in (A) negative control sample and CRLF2pos patients with (B) bimodal dim pattern (low expression on the blast subclone); (C) heterogeneous low expression (negative to dim) in some blasts; (D) homogeneous dim expression on all blasts; (E) bimodal strong pattern (high expression on the blasts subclone); and (F) homogeneous strong expression on all blasts. Note: The rectangles represent blasts positive for CRLF2; red - leukemic blasts; green - mature B-cells (CRLF2-negative), gray - other cells (CRLF2-negative).
Figure 3
Figure 3
Comparison of MRD levels at (A, C, E) day 15 and (B, D, F) day 33 in patients with (A-B) surface CRLF2 expression, (C-D) IKZF1 deletion and (E-F) CRLF2pos patients with IKZF1 deletion.
Figure 4
Figure 4. Survival outcomes in pediatric BCP-ALL patients based on the status of CRLF2 expression and IKZF1 deletions
The Kaplan-Meier survival curves show (A) overall survival (OS) and (B) relapse-free survival (RFS) of pediatric BCP-ALL patients based on the status of surface CRLF2 protein expression and IKZF1 deletions. Also included are tables showing survival estimates based on the Cox proportional hazard regression model for different categories of patients.
See this image and copyright information in PMC

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