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A brain organoid/ALL co-culture model reveals the AP-1 pathway as critically associated with CNS-involvement of BCP-ALL

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271998 | GEO | 2024/07/16

REPOSITORIES: GEO

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Project description:Background. Flow cytometry (FCM) identifies leukemic blasts in cerebrospinal fluid (CSF) in approximately 30% of children with acute lymphoblastic leukemia (ALL), whereas conventional cytospin preparations frequently miss such involvement. <br>Procedure. To explore biological properties of leukemic cells that migrate into central nervous system (CNS), we compared gene expression profiles of leukemic cells from 26 patients with CNS involvement and 138 patients without CNS leukemia as determined by FCM and/or cytospin preparations. Results were validated by real-time quantitative PCR (qPCR). <br>Results. We found the cysteine endopeptidase legumain (LGMN) that plays a role in hydrolysis of proteins and small molecules to be significantly differentially expressed between FCM+ and FCM- B-cell precursor (BCP) ALL patients. When LGMN expression was validated by qPCR it stayed differentially expressed between FCM+ and FCM- BCP-ALL patients (P=0.006), and also between FCM+ and cytospin-negative BCP-ALL patients (P=0.01). In multivariate regression analysis including sex, age and WBC, LGMN expression levels above population median were associated with an odds ratio of 9.1 for CNS involvement as determined by FCM compared with expression less than the median (95% CI, 1.26 to 65.50; P=0.03). Conclusions. The use of more sensitive methods for detecting and quantifying CNS involvement, such as FCM, may facilitate detection of markers of leukemia biology, such as LGMN, which could have therapeutical implications for future CNS-directed therapy.<br>FCM+: Patients had leukemic cells in the cerebrospinal fluid (CSF) detected by flow cytometry and no blood contamination. FCM-: Patients had no leukemic cells in the CSF detected by flow cytometry with or without blood contamination.<br>CNS1: No leukemic cells in CSF detected by cytospin examination with or without blood contamination and no other clinical signs of central nervous system (CNS) leukaemia. CNS2: CSF leukocyte count <5 x106/ÂµL with blasts on cytospin examination and no blood contamination. CNS3: CSF leukocyte count >5 x106/ÂµL with blasts on cytospin examination and no blood contamination, and/or cranial nerve palsy, and/or CNS leukaemia by neuroimaging.

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A brain organoid/ALL co-culture model reveals the AP-1 pathway as critically associated with CNS-involvement of BCP-ALL

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