Expression data for childhood BCP-ALL xenografts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58290 | GEO | 2015/03/05
SECONDARY ACCESSION(S): PRJNA251907
REPOSITORIES: GEO
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Project description:Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2D cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3D co-culture model combining human brain organoids and BCP-ALL cells. We noticed signicantly higher engraftment of TCF3::PBX1+ leukemia cell lines and patient-derived xenograft (PDX) cells in human induced pluripotent stem cell (iPSC)-derived cerebral organoids when compared to cell lines derived from chronic myeloid leukemia (CML), a subtype typically not associated with CNS involvement. Next, to validate translatability between organoid co-culture model and in vivo murine models, we confirmed that targeting CNS leukemia relevant pathways like CD79a/Igα or CXCR4-SDF1 reduced the invasion of BCP-ALL cells into organoids. RNA sequencing and further validations of organoid-invading leukemia cells compared to the non-invaded fraction revealed significant upregulation of the AP-1 transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in ALL-PDX cells recovered from the CNS compared to spleen blasts of mice transplanted with TCF3::PBX1+ PDX cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1-gene JUN in patients initially diagnosed as CNS-positive compared to CNS-negative cases as well as CNS-relapse cases in a cohort of 100 BCP-ALL patients. Our results suggest iPSC-derived brain organoids as a novel model to investigate CNS-involvement and identify the AP-1 pathway as a critical driver of CNS-disease in BCP-ALL.
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Project description:Expression data for childhood BCP-ALL xenografts
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Project description:Leukemic cells from either peripheral blood or bone marrow were obtained from 6 patients with acute lymphocytic leukemia. These cells were used to generate mouse xenografts and a comparison was made between those two sample sources.
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Project description:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two 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), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression 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 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two 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. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays
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