Clinical characterization and prognosis of T cell acute lymphoblastic leukemia with high CRLF2 gene expression in children

Autoři: Mingmin Wang aff001;  Jinquan Wen aff004;  Yuxia Guo aff001;  Yali Shen aff001;  Xizhou An aff001;  Yanni Hu aff001;  Jianwen Xiao aff001
Působiště autorů: Department of Hematology, Children’s Hospital of Chongqing Medical University, Chongqing, P.R. China aff001;  Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P.R. China aff002;  Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China aff003;  Department of Hematology, Children’s Hospital of Xianyang, Xi’an, P.R. China aff004;  China International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, P.R. China aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed. In this study, CRLF2 mRNA expression levels and clinical and laboratory parameters in 63 pediatric T-ALL patients were detected at the Children's Hospital of Chongqing Medical University and Children’s Hospital of Xianyang between February 2015 and June 2018. The patients were treated according to the modified St. Jude TXV ALL protocol, and early treatment responses (bone marrow smear and MRD level) and prognoses in the enrolled patients were assessed. CRLF2 overexpression was detected in 21/63 (33.33%) patients. Statistical differences were not found for clinical or laboratory parameters (including sex, age, initial WBC count, incidence mediastinal involvement, abnormal karyotype and fusion genes) between patients with high CRLF2 expression and patients with low expression of CRLF2 (P>0.05). One patient died of tumor lysis syndrome and renal failure, and the treatment response was monitored on day 19 (TP1) of remission in 62 patients. One patient quit treatment because of family decisions, and 61 patients underwent treatment response evaluation on day 46 (TP2) of remission. Significant differences were not found between patients with high CRLF2 expression and patients with low CRLF2 expression in terms of the treatment responses at TP1 or TP2 (P>0.05). Following October 2018, 12 patients among the 61 evaluable patients relapsed (relapse rate: 19.67%), 3 patients died from chemotherapy, and the treatment-related mortality (TRM) rate was 4.92%. Secondary tumors occurred in 1 patient. The 3-year prospective EFS rate was 54.1±11.2% and 77.7±6.6% for the 61 evaluable patients and 58 patients without TRM. Patients with low CRLF2 expression had longer EFS durations than patients with high CRLF2 expression (61 evaluable patients: 35.91± 2.38 months vs 23.43± 2.57 months; 58 patients without TRM: 37.86± 2.08 months vs 24.55±2.43 months, P<0.05). CRLF2 expression levels were also monitored in 13 patients at TP1 and TP2, and the MRD level did not vary with the CRLF2 expression level. Our data suggest that clinical features, laboratory findings and treatment responses in the pediatric T-ALL population do not vary based on the overexpression of CRLF2 but that CRLF2 overexpression can contribute to a high risk of relapse in pediatric T-ALL. Thus, CRLF2 expression levels should not be used as biomarkers for monitoring MRD.

Klíčová slova:

Acute lymphoblastic leukemia – Cancer treatment – Clinical laboratories – Hyperexpression techniques – Chemotherapy – Karyotypes – Pediatrics – Fusion genes


1. Yeh TC, Liang DC, Liu HC, Jaing TH, Chen SH, Hou JY, et al. Clinical and biological relevance of genetic alterations in pediatric T-cell acute lymphoblastic leukemia in Taiwan. Pediatr Blood Cancer. 2019 Jan; 66(1):e27496. doi: 10.1002/pbc.27496 Epub 2018 Oct 2. 30280491

2. Barba P, Morgades M, Montesinos P, Gil C, Fox ML, Ciudad, et al. Increased Survival due to Lower Toxicity for High Risk T-cell Acute Lymphoblastic Leukemia Patients in 2 consecutive Pediatric-Inspired PETHEMA Trials. Eur J Haematol. 2019; 1:79–86.

3. Sayed DM, Sayed HAR, Raslan HN, Ali AM, Zahran A, AI-Hayek R, et al. Outcome and Clinical Significance of Immunophenotypic Markers Expressed in Different Treatment Protocols of Pediatric Patients With T-ALL in Developing Countries. Clin Lymphoma Myeloma Leuk. 2018; 17: 443–449.

4. Francis OL, Milford TA, Martinez SR, Baez I, Costs JS, Mayagoitia, et al. A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. Haematologica. 2016; 101: 417–426. doi: 10.3324/haematol.2015.125336 26611474

5. Tatsuno K, Fujiyama T, Yamaguchi H, Waki M, Tokura Y. TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis. J Invest Dermatol. 2015; 135: 3017–3024. doi: 10.1038/jid.2015.318 26288354

6. Lin SC, Huang JJ, Wang JY, Chuang HC, Chiang BL, Ye YL. Upregulated thymic stromal lymphopoietin receptor expression in children with asthma. Eur J Clin Invest. 2016; 46: 511–519. doi: 10.1111/eci.12623 26999524

7. Chiaretti S, Brugnoletti F, Messina M, Paoloni F, Fedullo AL, Piciocchi A, et al. CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities. Leuk Res. 2016; 41:36–42. doi: 10.1016/j.leukres.2015.11.018 26754556

8. Hanada I, Terui K, Ikeda F, Toki T, Kanezaki R, Sato T, et al. Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes Chromosomes Cancer. 2014; 53: 902–910. doi: 10.1002/gcc.22201 25044358

9. Yamashita Y, Shimada A, Yamada T, Yamaji K, Hori T, Tsurusawa M, et al. IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR-ABL1- negative high-risk B-cell precursor acute lymphoblastic leukemia. Pediatric Blood Cancer. 2013; 10: 1587–1592.

10. Palmi C, Savino AM, Silvestri D, Bronzini I, Cario G, Paganin M, et al. CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia. Oncotarget. 2016; 13: 59260–59272.

11. Pui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia. 2017; 31:333–339. doi: 10.1038/leu.2016.234 27560110

12. Shago M. Recurrent Cytogenetic Abnormalities in Acute Lymphoblastic Leukemia. Methods Mol Biol. 2017; 1541:257–278. doi: 10.1007/978-1-4939-6703-2_21 27910029

13. Pallisgaard N, Hokland P, Riishøj DC, Pedersen B, Jørgensen P. Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia. Blood. 1998; 92: 574–588. 9657758

14. Kim B, Cho YU, Bae MH, Jang S, Seo EJ, Chi HS, et al. The added values of multiplex reverse transcriptase-PCR followed by mutation screening in the initial evaluation of acute leukemia. Int J Lab Hematol.2016; 38: 444–453. doi: 10.1111/ijlh.12521 27321126

15. Marjerrison S, Antillon F, Fu L, Martinez R, Vasquez R, Bonilla M, et al. Outcome of children treated for relapsed acute lymphoblastic leukemia in Central America. Cancer. 2013; 119: 1277–1283. doi: 10.1002/cncr.27846 23165914

16. Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003; 19: 3616–3622.

17. Tamaki K, Morishima S, Nomura S, Nishi Y, Nakachi S, Kitamura S,et al. Evaluation of two prognostic indices for adult T-cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan. Cancer Sci. 2018; 109: 2286–2293. doi: 10.1111/cas.13641 29772611

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2019 Číslo 12
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