Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia

Touw, IP; Pouwels, K; Agthoven, Ton van; Gurp, R van; Budel, Leo M.; Hoogerbrugge, Hans; Delwel, Ruud; Goodwin, Raymond G.; Namen, Anthony E.; Löwenberg, Bob

doi:10.1182/blood.v75.11.2097.bloodjournal75112097

Cited by 26 publications

(29 citation statements)

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“…7 IL-7 is present in the microenvironments where the malignant T cells arise and develop, 8 and most human primary T-cell acute lymphoblastic leukemia (T-ALL) samples express IL-7Ra 9 and proliferate in vitro in response to IL-7. [10][11][12] Accordingly, we have shown that IL-7 accelerates human T-ALL development in vivo. 13 However, the exact molecular mechanisms by which this microenvironmental factor contributes to T-ALL cell viability and proliferation remain only partially characterized.…”

Section: Introductionmentioning

confidence: 99%

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

et al. 2018

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T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27 and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase Pharmacological inhibition of PIM1 abrogates IL-7-mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R.

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Section: Introductionmentioning

confidence: 99%

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

et al. 2018

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“…No. 14 was cultured in RPMI-1640, whereas the human BM stromal line KM-102:2 a gift of Dr K. Harigaya (Chiba University, Japan), was kept in Iscove's modified Dulbecco's medium (IMDM; GIBCO; Cat. No.…”

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confidence: 99%

Bone marrow-derived stromal cells prevent apoptotic cell death in B- lineage acute lymphoblastic leukemia

Manabe

Coustan‐Smith

Behm

et al. 1992

Blood

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Establishing requirements for the survival of human immature B cells in vitro has proved elusive. In this article, we report prolonged survival of B-lineage leukemic cells on ‘feeder layers’ of bone marrow (BM)- derived stromal cells in a serum-free environment. In 15 of 18 cases of B-lineage acute lymphoblastic leukemia (ALL), there was a greater than 50% decrease in the number of viable cells after 72 hours of culture in medium alone. Cell loss was preceded by molecular and cellular changes characteristic of programmed cell death, or apoptosis, and was not suppressed by adding interleukin-7 to the tissue culture medium. By contrast, the use of allogeneic BM stromal cells as feeder layers prevented apoptosis in 10 of 12 cases of ALL, leading to extended survival of the blast cells. This method was not successful when the allogeneic marrow cells were replaced with established cell lines. In six of eight cases in which the numbers of intact CD19+ lymphoblasts were counted by flow cytometry after 7 days of culture, the proportion of such cells recovered in the presence of BM stromal cells was 68.8% to 124.7% (median, 95.3%) of that originally seeded, as opposed to the 0.3% to 15.9% fraction (median, 0.7%) obtained in the absence of stromal cells. Survival requirements of the B-lineage lymphoblasts appeared to be heterogeneous, as cells from 3 of the 18 cases studied showed no signs of apoptosis in serum-free tissue culture medium that lacked BM stromal cells. The only cells not giving rise to viable cultures were from two hyperdiploid (greater than 50 chromosomes) cases with identical karyotypes. The serum-free assay described here can be used to compare the survival requirements of normal and leukemic B-cell progenitors as well as to identify the molecules involved in the interaction between BM stroma and immature B cells.

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“…Oncogenesis IL-7/IL-7R signaling has a major impact in the survival and proliferation of T-ALL cells in vitro (e.g. Touw et al, 1990;Dibirdik et al, 1991;Barata et al, 2004a;Barata et al, 2004b) and leukemia expansion in vivo (Silva et al, 2011). Oncogenic IL7R activating mutations occur in T-ALL.…”

Section: T-cell Acute Lymphoblastic Leukemia (T-all)mentioning

confidence: 99%

IL7R (interleukin 7 receptor)

Ribeiro¹,

Barata²

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia

Cited by 26 publications

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STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

Bone marrow-derived stromal cells prevent apoptotic cell death in B- lineage acute lymphoblastic leukemia

IL7R (interleukin 7 receptor)

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