Evaluating the Role of Cytokine Receptor-like Factor 2 and Janus Kinase 2 in Adult Acute Lymphoblastic Leukemia

Authors

  • Naglaa M. Hassan Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
  • Mona S. El Ashry Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
  • Mona Abdellateif Department of Medical Biochemistry and Molecular Biology, Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-5510-4435
  • Reem Nabil Hassan Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt https://orcid.org/0000-0001-8542-9495

DOI:

https://doi.org/10.3889/oamjms.2022.9139

Keywords:

Acute lymphoblastic leukemia, CRLF2, JAK2, Survival, Adult, Outcome

Abstract

AIM: The aim of the present study was to assess the diagnostic, prognostic, and predictive roles of the cytokine receptor-like factor 2 (CRLF2) and the Janus Kinase 2 (JAK2) genes expression in adult acute lymphoblastic leukemia (ALL) patients.

METHODS: The expression levels of CRLF2 and JAK2 genes were evaluated in the bone marrow (BM) samples of 105 adult ALL patients, compared to 12 healthy controls. The data were correlated to the patients’ relevant clinic-pathological features, response to treatment and survival rates.

RESULTS: There was a significant overexpression of JAK2 in ALL patients compared to the control group [0.04 (0–160.8) and 0.006 (0–0.009), respectively, p < 0.001]. Similarly, CRLF2 was overexpressed in ALL patients in comparison to control subjects [0.008 (0–78.2) and 0.0005 (0–0.006), respectively, p < 0.001]. The sensitivity, specificity, and the area under curve (AUC) for JAK2 were 78.1%, 81.8%, and 0.796, respectively (p < 0.001), and that of CRLF2 were 92.4%, 90.9%, 0.958, respectively (p < 0.001). When combining both JAK2 and CRLF2 for the diagnosis of ALL patients, it revealed 90.9% sensitivity, 91.4% specificity, and AUC of 0.957 (p < 0.001). The JAK2, CRLF2, or their combined expression associated significantly with the increased expression of MHC-II (p = 0.015, 0.001, and 0.004, respectively). However, they had no significant impact on patients’ response to treatment, overall (OS), and disease-free survival (DFS) rates (p > 0.05 for all).

CONCLUSION: JAK2 and CRLF2 could be a potential useful diagnostic molecular marker for ALL patients, which allow them to be successful targets for ALL therapy.

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References

Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381(9881):1943-55. https://doi.org/10.1016/s0140-6736(12)62187-4 PMid:23523389 DOI: https://doi.org/10.1016/S0140-6736(12)62187-4

DeAngelo DJ, Jabbour E, Advani A. Recent advances in managing acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:330-42. https://doi.org/10.1200/edbk_280175 PMid:32421447 DOI: https://doi.org/10.1200/EDBK_280175

Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: A children’s oncology group study. J Clin Oncol. 2009;27(31):5175-81. https://doi.org/10.1200/jco.2008.21.2514 PMid:19805687 DOI: https://doi.org/10.1200/JCO.2008.21.2514

Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017;129(9):1113-23. https://doi.org/10.1182/blood-2016-10-706465 PMid:28115373 DOI: https://doi.org/10.1182/blood-2016-10-706465

Fogelstrand L, Staffas A, Wasslavik C, Sjögren H, Söderhäll S, Frost BM, et al. Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T‐all treated according to the NOPHO ALL‐1992 and ALL‐2000 protocols. Pediatr Blood Cancer. 2014;61(3):424-30. https://doi.org/10.1002/pbc.24803 PMid:24424791 DOI: https://doi.org/10.1002/pbc.24803

Meyer LK, Delgado-Martin C, Maude SL, Shannon KM, Teachey DT, Hermiston ML. CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. PLoS One. 2019;14(7):e0220026. https://doi.org/10.1371/journal.pone.0220026 PMid:31318944 DOI: https://doi.org/10.1371/journal.pone.0220026

Roberts KG, Mullighan CG. Genomics in acute lymphoblastic leukaemia: Insights and treatment implications. Nat Rev Clin Oncol. 2015;12(6):344. https://doi.org/10.1038/nrclinonc.2015.38 PMid:25781572 DOI: https://doi.org/10.1038/nrclinonc.2015.38

Herold T, Schneider S, Metzeler KH, Neumann M, Hartmann L, Roberts KG, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica. 2017;102(1):130-8. https://doi.org/10.3324/haematol.2015.136366 PMid:27561722 DOI: https://doi.org/10.3324/haematol.2015.136366

Rochman Y, Kashyap M, Robinson GW, Sakamoto K, Gomez-Rodriguez J, Wagner KU, et al. Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. Proc Natl Acad Sci. 2010;107(45):19455-60. https://doi.org/10.1073/pnas.1008271107 PMid:20974963 DOI: https://doi.org/10.1073/pnas.1008271107

Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci. 2010;107(1):252-7. https://doi.org/10.1073/pnas.0911726107 PMid:20018760 DOI: https://doi.org/10.1073/pnas.0911726107

Fang Q, Zhao X, Li Q, Li Y, Liu K, Tang K, et al. IKZF1 alterations and expression of CRLF2 predict prognosis in adult Chinese patients with B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2017;58(1):127-37. https://doi.org/10.1080/10428194.2016.1180682 PMid:27157479 DOI: https://doi.org/10.1080/10428194.2016.1180682

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. https://doi.org/10.1016/j.leukres.2015.11.018 PMid:26754556 DOI: https://doi.org/10.1016/j.leukres.2015.11.018

Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: A report from the International BFM Study Group. Blood. 2010;115(5):1006-17. https://doi.org/10.1016/s1040-1741(10)79520-8 PMid:19965641 DOI: https://doi.org/10.1016/S1040-1741(10)79520-8

Tasian SK, Doral MY, Borowitz MJ, Wood BL, Chen IM, Harvey RC, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833-42. https://doi.org/10.1182/blood-2011-12-389932 PMid:22685175 DOI: https://doi.org/10.1182/blood-2011-12-389932

Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, et al. Rearrangement of CRLF2 in B-progenitor-and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet. 2009;41(11):1243-6. https://doi.org/10.1038/ng.469 PMid:19838194 DOI: https://doi.org/10.1038/ng.469

Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome. Lancet. 2008;372(9648):1484-92. https://doi.org/10.1016/s0140-6736(08)61341-0 PMid:18805579 DOI: https://doi.org/10.1016/S0140-6736(08)61341-0

Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol. 2009;144(6):930-2. https://doi.org/10.1111/j.1365-2141.2008.07552.x PMid:19120350 DOI: https://doi.org/10.1111/j.1365-2141.2008.07552.x

Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci. 2009;106(23):9414-8. https://doi.org/10.1073/pnas.0811761106 PMid:19470474 DOI: https://doi.org/10.1073/pnas.0811761106

Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC, et al. Long-term results of St Jude total therapy studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia. 2010;24(2):371-82. https://doi.org/10.1038/leu.2009.252 PMid:20010620 DOI: https://doi.org/10.1038/leu.2009.252

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25(4):402-8. https://doi.org/10.1006/meth.2001.1262 PMid:11846609 DOI: https://doi.org/10.1006/meth.2001.1262

Konoplev S, Lu X, Konopleva M, Jain N, Ouyang J, Goswami M, et al. CRLF2-positive B-cell acute lymphoblastic leukemia in adult patients: A single-institution experience. Am J Clin Pathol. 2017;147(4):357-63. https://doi.org/10.1093/ajcp/aqx005 PMid:28340183 DOI: https://doi.org/10.1093/ajcp/aqx005

Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32(27):3012-20. https://doi.org/10.1200/jco.2014.55.4105 PMid:25049327 DOI: https://doi.org/10.1200/JCO.2014.55.4105

Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115(26):5312-21. https://doi.org/10.1182/blood-2009-09-245944 PMid:20139093 DOI: https://doi.org/10.1182/blood-2009-09-245944

Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153-66. https://doi.org/10.3410/f.717954414.793460270 PMid:22897847 DOI: https://doi.org/10.3410/f.717954414.793460270

Sadras T, Heatley SL, Kok CH, Dang P, Galbraith KM, McClure BJ, et al. Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. Cancer Lett. 2017;408:92-101. https://doi.org/10.1016/j.canlet.2017.08.034 PMid:28866095 DOI: https://doi.org/10.1016/j.canlet.2017.08.034

Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013;32(21):2601-13. https://doi.org/10.1038/onc.2012.347 PMid:22869151 DOI: https://doi.org/10.1038/onc.2012.347

Tasian SK, Loh ML. Understanding the biology of CRLF2- overexpressing acute lymphoblastic leukemia. Crit Rev Oncog. 2011;16(1-2):13-24. https://doi.org/10.1615/critrevoncog.v16.i1-2.30 PMid:22150304 DOI: https://doi.org/10.1615/CritRevOncog.v16.i1-2.30

Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688-98. https://doi.org/10.1182/blood-2009-03-208397 PMid:19641190 DOI: https://doi.org/10.1182/blood-2009-03-208397

Gu Y, Wu YJ, Han Q, Zhou XL, Qiao C, Li JY, et al. Characteristics and clinical significance of CRLF2 mutations in adult acute lymphoblastic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017;25(2):328-33. PMid:28446270

Ensor HM, Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, et al. Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: Results from the MRC ALL97 clinical trial. Blood. 2011;117(7):2129-36. https://doi.org/10.1182/blood-2011-03-344689 DOI: https://doi.org/10.1182/blood-2010-07-297135

van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with Bcell precursor ALL. Blood. 2013;122(15):2622-9. https://doi.org/10.1182/blood-2012-10-462358 PMid:23974192 DOI: https://doi.org/10.1182/blood-2012-10-462358

Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JP, Beverloo HB, et al. Outcome in children with Down’s syndrome and acute lymphoblastic leukemia: Role of IKZF1 deletions and CRLF2 aberrations. Leukemia. 2012;26(10):2204-11. https://doi.org/10.1038/leu.2012.84 PMid:22441210 DOI: https://doi.org/10.1038/leu.2012.84

Attarbaschi A, Morak M, Cario G, Cazzaniga G, Ensor HM, te Kronnie T, et al. Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: A comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups. Br J Haematol. 2012;158(6):772-7. https://doi.org/10.1111/j.1365-2141.2012.09221.x PMid:22816614 DOI: https://doi.org/10.1111/j.1365-2141.2012.09221.x

Chen H, Wang XJ, Liu S, Yuan FF, Ai H, Chen L, et al. The expression of CRLF2 in adult Ph negative acute B lymphocytic leukemia and its prognostic significance. Zhonghua Xue Ye Xue Za Zhi. 2018;39(10):822-7. PMid:30369203

Cario G, Zimmermann M, Romey R, Gesk S, Vater I, Harbott J, et al. Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood. 2010;115(26):5393-7. https://doi.org/10.1182/blood-2009-11-256131 PMid:20378752 DOI: https://doi.org/10.1182/blood-2009-11-256131

Palmi C, Vendramini E, Silvestri D, Longinotti G, Frison D, Cario G, et al. Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia. 2012;26(10):2245-53. https://doi.org/10.1038/leu.2012.101 PMid:22484421 DOI: https://doi.org/10.1038/leu.2012.101

Chen IM, Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: A Children’s oncology group study. Blood. 2012;119(15):3512-22. https://doi.org/10.1016/j.yonc.2012.07.023 DOI: https://doi.org/10.1182/blood-2011-11-394221

Moorman AV. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2016;101(4):407-16. https://doi.org/10.3324/haematol.2015.141101 PMid:27033238 DOI: https://doi.org/10.3324/haematol.2015.141101

Holling TM, Schooten E, Langerak AW, van den Elsen PJ. Regulation of MHC class II expression in human T-cell malignancies. Blood. 2004;103(4):1438-44. https://doi.org/10.1182/blood-2003-05-1491 PMid:14563641 DOI: https://doi.org/10.1182/blood-2003-05-1491

Garand R, Vannier JP, Bene MC, Faure G, Favre M, Bernard A. Comparison of outcome, clinical, laboratory, and immunological features in 164 children and adults with T-ALL: The Groupe d’Etude Immunologique des Leucemies. Leukemia. 1990;4:739-44. PMid:2232884

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Published

2022-04-19

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1.
Hassan NM, El Ashry MS, Abdellateif M, Hassan RN. Evaluating the Role of Cytokine Receptor-like Factor 2 and Janus Kinase 2 in Adult Acute Lymphoblastic Leukemia. Open Access Maced J Med Sci [Internet]. 2022 Apr. 19 [cited 2024 Mar. 29];10(B):1622-31. Available from: https://oamjms.eu/index.php/mjms/article/view/9139