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Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients


Traxel, Sabrina; Schadt, Linda; Eyer, Tatjana; Mordasini, Vanessa; Gysin, Claudine; Munthe, Ludvig A; Niggli, Felix; Nadal, David; Bürgler, Simone (2019). Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients. Oncogene, 38(13):2420-2431.

Abstract

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

Abstract

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Genetics, Cancer Research, Molecular Biology
Language:English
Date:1 March 2019
Deposited On:04 Feb 2019 11:52
Last Modified:29 Mar 2019 02:04
Publisher:Nature Publishing Group
ISSN:0950-9232
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41388-018-0594-4
PubMed ID:30532071

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