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Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions.
Cancer Lett 2017; 408:92-101CL

Abstract

CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking.

Authors+Show Affiliations

Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.Molecular Diagnostics Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, NSW, Australia.Molecular Diagnostics Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, NSW, Australia.Department of Genetic Pathology, SA Pathology, Adelaide, SA, Australia.SA Pathology at Women's & Children's Hospital, Adelaide, SA, Australia; Australian Genomic Health Alliance, Adelaide, SA, Australia.SA Pathology at Women's & Children's Hospital, Adelaide, SA, Australia.The University of Queensland Diamantina Institute, UQ Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia; Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; Department of Haematology, SA Pathology, Adelaide, SA, Australia.Department of Haematology, SA Pathology, Adelaide, SA, Australia.Molecular Diagnostics Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, NSW, Australia; Australian Genomic Health Alliance, Adelaide, SA, Australia; School of Women's and Children's Health, Medicine, University of NSW, Sydney, NSW, Australia.Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; Australian Genomic Health Alliance, Adelaide, SA, Australia. Electronic address: deborah.white@sahmri.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28866095

Citation

Sadras, Teresa, et al. "Differential Expression of MUC4, GPR110 and IL2RA Defines Two Groups of CRLF2-rearranged Acute Lymphoblastic Leukemia Patients With Distinct Secondary Lesions." Cancer Letters, vol. 408, 2017, pp. 92-101.
Sadras T, Heatley SL, Kok CH, 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.
Sadras, T., Heatley, S. L., Kok, C. H., Dang, P., Galbraith, K. M., McClure, B. J., ... White, D. L. (2017). Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. Cancer Letters, 408, pp. 92-101. doi:10.1016/j.canlet.2017.08.034.
Sadras T, 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 11 1;408:92-101. PubMed PMID: 28866095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. AU - Sadras,Teresa, AU - Heatley,Susan L, AU - Kok,Chung H, AU - Dang,Phuong, AU - Galbraith,Kate M, AU - McClure,Barbara J, AU - Muskovic,Walter, AU - Venn,Nicola C, AU - Moore,Sarah, AU - Osborn,Michael, AU - Revesz,Tamas, AU - Moore,Andrew S, AU - Hughes,Timothy P, AU - Yeung,David, AU - Sutton,Rosemary, AU - White,Deborah L, Y1 - 2017/09/01/ PY - 2017/06/24/received PY - 2017/08/15/revised PY - 2017/08/24/accepted PY - 2017/9/4/pubmed PY - 2017/11/2/medline PY - 2017/9/4/entrez KW - Genomics KW - JAK2 KW - Lymphoblastic leukemia SP - 92 EP - 101 JF - Cancer letters JO - Cancer Lett. VL - 408 N2 - CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/28866095/Differential_expression_of_MUC4_GPR110_and_IL2RA_defines_two_groups_of_CRLF2_rearranged_acute_lymphoblastic_leukemia_patients_with_distinct_secondary_lesions_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(17)30521-9 DB - PRIME DP - Unbound Medicine ER -