TY - JOUR
T1 - TSLP-Induced Alterations of Multiple Signaling Pathways in Primary CRLF2 B-ALL Xenografts
AU - Shiraz, Parveen
AU - Francis, Olivia
AU - Delgado, Ineavely
AU - Martinez, Shannalee R
AU - Coats, Jacqueline
AU - Conception, Katherine Salcedo
AU - Mayagoitia, Karina
AU - Ginelli, Elizabeth
AU - Milford, Terry-Ann
AU - Fisher, Ross
AU - Morris, Christopher L.
AU - Zhang, Xiao-bing
AU - Su, Ruijun
AU - Dovat, Sinisa
AU - Payne, Kimberly J
N1 - B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects leading to overexpression of CRLF2 (CRLF2 B-ALL) is associated with a high relapse rate and poor prognosis. CRLF2 B-ALL comprises approximately half of the high risk B-ALL characterized by a gene expression profile that is similar to that of Philadelphia chromosome-positive ALL (Ph-like B-ALL).
PY - 2014/12/6
Y1 - 2014/12/6
N2 - B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects leading to overexpression of CRLF2 (CRLF2 B-ALL) is associated with a high relapse rate and poor prognosis. CRLF2 B-ALL comprises approximately half of the high risk B-ALL characterized by a gene expression profile that is similar to that of Philadelphia chromosome-positive ALL (Ph-like B-ALL). In pediatric patients, CRLF B-ALL occurs 5 times more frequently among children of Hispanic and Native American ethnicity and is a major contributor to health disparities in ALL. CRLF2 (cytokine related ligand factor 2) together with the IL-7 receptor alpha chain, forms a receptor complex that is activated by the cytokine, TSLP (Thymic Stromal Lymphopoietin). Activation of CRLF by TSLP leads to downstream JAK-STAT5 and mTOR pathway phosphorylation even in CRLF2 B-ALL harboring activating JAK mutations. We found that primary human marrow (BM) stromal cells express TSLP (RT-PCR and ELISA) and thus provide an in vivo source of TSLP to activate CRLF2 B-ALL cells. Our next step was to develop a xenograft model system to identify the in vivo CRLF2-mediated gene expression profile and disease mechanisms that might contribute to poor prognosis. Unlike most other cytokines, mouse TSLP is species-specific and thus does not activate the human CRLF2 receptor complex. We engineered immune-deficient NOD/SCID IL-2Rγ null (NSG) mice to express normal serum levels (~20 pg/ml) of human TSLP (hTSLP+ mice), as well as control mice that lack human TSLP (hTSLP– mice). Primary human CRLF2 B-ALL were injected into hTSLP+ and hTSLP– mice and expanded for 10 weeks in vivo. Whole genome microarray was performed on CRLF2 B-ALL cells isolated by magnetic separation from the BM of hTSLP+ and hTSLP- xenograft mice. Evaluation of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis showed that genes downstream of mTOR pathway activation were upregulated in hTSLP+ as compared to hTSLP- mice, confirming hTSLP activity in the hTSLP+ xenograft mice. Microarray identified 280 genes that are upregulated and 281 genes that are downregulated (> 1.7 fold; p
AB - B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects leading to overexpression of CRLF2 (CRLF2 B-ALL) is associated with a high relapse rate and poor prognosis. CRLF2 B-ALL comprises approximately half of the high risk B-ALL characterized by a gene expression profile that is similar to that of Philadelphia chromosome-positive ALL (Ph-like B-ALL). In pediatric patients, CRLF B-ALL occurs 5 times more frequently among children of Hispanic and Native American ethnicity and is a major contributor to health disparities in ALL. CRLF2 (cytokine related ligand factor 2) together with the IL-7 receptor alpha chain, forms a receptor complex that is activated by the cytokine, TSLP (Thymic Stromal Lymphopoietin). Activation of CRLF by TSLP leads to downstream JAK-STAT5 and mTOR pathway phosphorylation even in CRLF2 B-ALL harboring activating JAK mutations. We found that primary human marrow (BM) stromal cells express TSLP (RT-PCR and ELISA) and thus provide an in vivo source of TSLP to activate CRLF2 B-ALL cells. Our next step was to develop a xenograft model system to identify the in vivo CRLF2-mediated gene expression profile and disease mechanisms that might contribute to poor prognosis. Unlike most other cytokines, mouse TSLP is species-specific and thus does not activate the human CRLF2 receptor complex. We engineered immune-deficient NOD/SCID IL-2Rγ null (NSG) mice to express normal serum levels (~20 pg/ml) of human TSLP (hTSLP+ mice), as well as control mice that lack human TSLP (hTSLP– mice). Primary human CRLF2 B-ALL were injected into hTSLP+ and hTSLP– mice and expanded for 10 weeks in vivo. Whole genome microarray was performed on CRLF2 B-ALL cells isolated by magnetic separation from the BM of hTSLP+ and hTSLP- xenograft mice. Evaluation of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis showed that genes downstream of mTOR pathway activation were upregulated in hTSLP+ as compared to hTSLP- mice, confirming hTSLP activity in the hTSLP+ xenograft mice. Microarray identified 280 genes that are upregulated and 281 genes that are downregulated (> 1.7 fold; p
UR - http://www.bloodjournal.org/content/124/21/3783?sso-checked=true
UR - https://ashpublications.org/blood/article/124/21/3783/115191/TSLP-Induced-Alterations-of-Multiple-Signaling
UR - https://www.mendeley.com/catalogue/e698e058-ed51-35d5-bfca-6a7def40b7d0/
U2 - 10.1182/blood.V124.21.3783.3783
DO - 10.1182/blood.V124.21.3783.3783
M3 - Meeting abstract
VL - 124
SP - 3783
EP - 3783
JO - Blood
JF - Blood
IS - 21
ER -