Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia

Russell, Lisa J., Capasso, Melania, Vater, Inga, Bernard, Olivier A., Chandrasekaran, Thiruppavaii, Griffith, Mike, Irving, Julie, Kearney, Lyndal, Moorman, Anthony V., Rand, Vikki, Strefford, Jonathan C., Dyer, Martin J. S., Siebert, Reiner, Harrison, Christine J., Takashi, Akasaka, Calasanz, Maria Jose, Chapiro, Elise, Gesk, Stephan, Guttery, David S., Haferlach, Claudia, Harder, Lana, Heidenreich, Olaf, Nguyen-Khac, Florence, Machado, Lee, Minto, Lynne, Majid, Aneela, Morrison, Heather, Schwab, Claire and Tönnies, Holger (2009) Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood, 114 (13), 2688-2698. (doi:10.1182/blood-2009-03-208397).

Abstract

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.

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Contributors

Author: Jonathan C. Strefford

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