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

Agata Pastorczak _, Lukasz Sedek, Marcin Braun, Joanna Madzio, Alicja Sonsala, Magdalena Twardoch, Wojciech Fendler, Karin Nebral, Joanna Taha, Marta Bielska, Patryk Gorniak, Magdalena Romiszewska, Michal Matysiak, Katarzyna Derwich, Monika Lejman, Jerzy Kowalczyk, Wanda Badowska, Maciej Niedzwiecki, Bernarda Kazanowska, Katarzyna Muszynska-Roslan, Grazyna Sobol-Milejska, Grazyna Karolczyk, Andrzej Koltan, Tomasz Ociepa, Tomasz Szczepanski and Wojciech Młynarski

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Oncotarget. 2018; 9:25971-25982. https://doi.org/10.18632/oncotarget.25411

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Abstract

Agata Pastorczak1,*, Lukasz Sedek2,*, Marcin Braun1,3,4, Joanna Madzio1,3, Alicja Sonsala2, Magdalena Twardoch2, Wojciech Fendler1,5, Karin Nebral6, Joanna Taha1, Marta Bielska1, Patryk Gorniak7, Magdalena Romiszewska8, Michal Matysiak8, Katarzyna Derwich9, Monika Lejman10, Jerzy Kowalczyk10, Wanda Badowska11, Maciej Niedzwiecki12, Bernarda Kazanowska13, Katarzyna Muszynska-Roslan14, Grazyna Sobol-Milejska15, Grazyna Karolczyk16, Andrzej Koltan17, Tomasz Ociepa18, Tomasz Szczepanski2,** and Wojciech Młynarski1,**

1Department of Pediatrics, Hematology, Oncology and Diabetology, Medical University of Łódź, Łódź, Poland

2Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland

3Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

4Department of Pathology, Chair of Oncology, Medical University of Łódź, Łódź, Poland

5Department of Biostatistics and Translational Medicine, Medical University of Łódź, Łódź, Poland

6Children’s Cancer Research Institute (CCRI), Vienna, Austria

7Institute of Hematology and Transfusion Medicine, Warsaw, Poland

8Department of Pediatrics, Oncology and Hematology, Medical University of Warsaw, Warsaw, Poland

9Department of Pediatric Hematology, Oncology, Transplantology, Medical University of Poznań, Poznań, Poland

10Department of Pediatric Hematology and Oncology, Medical University of Lublin, Lublin, Poland

11Department of Pediatric Hematology and Oncology, Children’s Hospital in Olsztyn, Olsztyn, Poland

12Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland

13Department of Transplantology, Pediatric Oncology and Hematology, Medical University of Wrocław, Wrocław, Poland

14Department of Pediatric Oncology, Medical University, Bialystok, Poland

15Department of Pediatrics, Medical University of Silesia, Katowice, Poland

16Regional Specialistic Pediatric Hospital, Kielce, Poland

17Department of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Mikolaj Kopernik University, Bydgoszcz, Poland

18Department of Pediatrics, Hematology and Oncology, Pomeranian Medical University, Szczecin, Poland

*These authors have contributed equally to this work

**Contributed equally as senior authors

Correspondence to:

Pastorczak Agata, email: [email protected]

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

Received: March 24, 2017    Accepted: April 27, 2018    Published: May 25, 2018

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.


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