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Status |
Public on Jul 17, 2020 |
Title |
Inhibition of Inflammatory Signaling in Pax5 Mutant Cells Mitigates B-cell leukemogenesis against leukemia |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions. PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers can be detected in neonatal blood spot samples of children who later developed B-cell precursor B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 loss results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. In vivo genetic downregulation of IL-6 in Pax5 mutant mice retards B-cell leukemogenesis. In vivo pharmacologic inhibition of IL-6 with a neutralizing IL-6 antibody in Pax5 mutant mice with B-ALL clears leukemic cells. This exciting novel IL 6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.
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Overall design |
We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions.
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Contributor(s) |
Isidro-Hernández M, Colino AM, Casado-García A, Raboso-Gallego J, Orfao A, Salas JR, Ribera JM, Zamora L, Blanco O, Alonso-López D, De Las Rivas J, Jiménez R, Criado FJ, Cenador MB, Ramírez-Orellana M, Cobaleda C, Vicente-Dueñas C, Sánchez-García I |
Citation(s) |
33154497 |
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Submission date |
Jul 16, 2020 |
Last update date |
Nov 16, 2020 |
Contact name |
Isidro Sánchez García |
E-mail(s) |
isg@usal.es
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Organization name |
Inst. de Inv. Biomédica de Salamanca (IBSAL). H. U. de Salamanca. Inst. de Biología Molecular y Celular del Cáncer (IBMCC).
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Department |
Centro de inv. del Cáncer (CIC).
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Street address |
Campus Miguel de Unamuno
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City |
Salamanca |
ZIP/Postal code |
E37007 |
Country |
Spain |
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Platforms (1) |
GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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Samples (22)
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GSM4675010 |
Bone Marrow proB and preB cells of WT mouse housed in CF, biological replicate 1 |
GSM4675011 |
Bone Marrow proB and preB cells of WT mouse housed in CF, biological replicate 2 |
GSM4675012 |
Bone Marrow proB and preB cells of WT mouse housed in CF, biological replicate 3 |
GSM4675013 |
Bone Marrow proB and preB cells of WT mouse housed in CF, biological replicate 4 |
GSM4675014 |
Bone Marrow proB and preB cells of WT mouse housed in SPF, biological replicate 1 |
GSM4675015 |
Bone Marrow proB and preB cells of WT mouse housed in SPF, biological replicate 2 |
GSM4675016 |
Bone Marrow proB and preB cells of WT mouse housed in SPF, biological replicate 3 |
GSM4675017 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in CF, biological replicate 1 |
GSM4675018 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in CF, biological replicate 2 |
GSM4675019 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in CF, biological replicate 3 |
GSM4675020 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in SPF, biological replicate 1 |
GSM4675021 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in SPF, biological replicate 2 |
GSM4675022 |
Bone Marrow proB and preB cells of healthy Pax5+/- mouse housed in SPF, biological replicate 3 |
GSM4675023 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 1 |
GSM4675024 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 2 |
GSM4675025 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 3 |
GSM4675026 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 4 |
GSM4675027 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 5 |
GSM4675028 |
Leukemic Pax5+/- mouse housed in CF, biological replicate 6 |
GSM4675029 |
Leukemic IL6+/-; Pax5+/- mouse housed in CF, biological replicate 1 |
GSM4675030 |
Leukemic IL6+/-; Pax5+/- mouse housed in CF, biological replicate 2 |
GSM4675031 |
Leukemic IL6+/-; Pax5+/- mouse housed in CF, biological replicate 3 |
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Relations |
BioProject |
PRJNA646739 |
Supplementary file |
Size |
Download |
File type/resource |
GSE154589_RAW.tar |
98.4 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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