Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions

Teresa Sadras, Susan L Heatley, Chung H Kok, Yen Dang, Kate M Galbraith, Barbara J McClure, Walter Muskovic, Nicola C. Venn, Sarah Moore, Michael Osborn, Tamas Revesz, Andrew S Moore, Timothy P Hughes, David Yeung, Rosemary Sutton, Deborah L White

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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.

LanguageEnglish
JournalCancer Letters
DOIs
Publication statusE-pub ahead of print - 30 Aug 2017

Keywords

  • Journal Article

Cite this

@article{0fdf280f3ff94248ad805f43d5d5a969,
title = "Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions",
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.",
keywords = "Journal Article",
author = "Teresa Sadras and Heatley, {Susan L} and Kok, {Chung H} and Yen Dang and Galbraith, {Kate M} and McClure, {Barbara J} and Walter Muskovic and Venn, {Nicola C.} and Sarah Moore and Michael Osborn and Tamas Revesz and Moore, {Andrew S} and Hughes, {Timothy P} and David Yeung and Rosemary Sutton and White, {Deborah L}",
note = "Copyright {\circledC} 2017. Published by Elsevier B.V.",
year = "2017",
month = "8",
day = "30",
doi = "10.1016/j.canlet.2017.08.034",
language = "English",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",

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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. / Sadras, Teresa; Heatley, Susan L; Kok, Chung H; Dang, Yen; Galbraith, Kate M; McClure, Barbara J; Muskovic, Walter; Venn, Nicola C.; Moore, Sarah; Osborn, Michael; Revesz, Tamas; Moore, Andrew S; Hughes, Timothy P; Yeung, David; Sutton, Rosemary; White, Deborah L.

In: Cancer Letters, 30.08.2017.

Research output: Contribution to journalArticle

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, Yen

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

N1 - Copyright © 2017. Published by Elsevier B.V.

PY - 2017/8/30

Y1 - 2017/8/30

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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.canlet.2017.08.034

DO - 10.1016/j.canlet.2017.08.034

M3 - Article

JO - Cancer Letters

T2 - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -