In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells

Yokoyama, Kazuaki; Yokoyama, Nozomu; Izawa, Kiyoko; Kotani, Ai; Harashima, Akira; Hozumi, Katsuto; Tojo, Arinobu

doi:10.1182/blood-2012-08-451278

Cited by 31 publications

(28 citation statements)

References 27 publications

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“…Although C7R expressing CAR T-cells do not show sustained autonomous/antigen independent growth and survival in vitro (Figure 1H,I), the transgene is modified from a class of constitutively active IL7R variants expressed in 10% of pre-T-cell acute leukemias (26), potentially increasing the risk of unwanted expansion. However, expression of this mutant receptor per se is not oncogenic, and transformation only occurs in association with multiple other driver mutations (27).…”

Section: Resultsmentioning

confidence: 99%

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells

et al. 2017

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Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but are associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL-7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Co-expressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and anti-tumor activity during repeated exposure to tumor cells, without T cell dysfunction or autonomous T cell growth. Furthermore, C7R co-expressing CAR-T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.

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Section: Resultsmentioning

confidence: 99%

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells

et al. 2017

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“…13,14,16 Therefore, we next sought to determine whether CK2 is also required in the context of the signals elicited by mutant IL7R. We found that CK2 inhibition prevented constitutive signaling downstream from mutated IL7R in DND-41 T-ALL cells, 16 as determined by the levels of phosphorylation of Akt and STAT5 ( Figure 5A). Accordingly, CX-4945 induced DND-41 cell death in a time-and dose-dependent manner ( Figure 5B,C), which was associated with high levels of apoptosis ( Figure 5D).…”

Section: Ck2 Inhibition Abrogates Constitutive Signaling and Viabilitmentioning

confidence: 99%

“…Around 10% of pediatric T-ALL patients display IL7R gain-of-function mutations, which lead to constitutive activation of downstream signaling and subsequent promotion of cell transformation and tumorigenesis. [12][13][14][15][16] Casein kinase 2 (CK2) is a ubiquitously expressed serine/threonine kinase, that is involved in the regulation of numerous cellular processes (e.g. cell cycle, gene expression and proliferation), through the modulation of the crosstalk between multiple signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity

et al. 2016

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I nterleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/ interleukin-7 receptor-mediated signaling. Casein kinase 2 pharmacological inhibition impaired signal transducer and activator of transcription 5 and phosphoinositide 3-kinase/v-Akt murine thymoma viral oncogene homolog 1 pathway activation triggered by interleukin-7 or by mutational activation of interleukin-7 receptor. By contrast, forced expression of casein kinase 2 augmented interleukin-7 signaling in human embryonic kidney 293T cells reconstituted with the interleukin-7 receptor machinery. Casein kinase 2 inactivation prevented interleukin-7-induced B-cell lymphoma 2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. Casein kinase 2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, casein kinase 2 was also required for the viability of mutant interleukin-7 receptor expressing leukemia T-cells. Overall, our study identifies casein kinase 2 as a major player in the effects of interleukin-7 and interleukin-7 receptor in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting casein kinase 2 in this malignancy.

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“…Aberrant expression of the receptors may be clonal or subclonal, preserved or altered between diagnosis and relapse 7,[19][20][21] . Two mouse models suggest that under specific conditions, expression of CRLF2 and/or IL7RA may initiate BCP-ALL [22][23][24] . Nevertheless, the relevance of these models to human BCP-ALL is unclear, due to major differences in the role of both IL7 and TSLP signaling in B-cell development in humans.…”

Section: Introductionmentioning

confidence: 99%

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Geron

Savino

Tal

et al. 2020

Preprint

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent preleukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphialike (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown. IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development. Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγ null mice resulted in B-cell differentiation arrest with aberrant expression of CD34 + and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34 + CD10 high CD19 low immunophenotype. The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Phlike BCP-ALL development from normal human hematopoietic progenitors in vivo.

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In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells

Abstract: Key Points Gain-of function mutation of IL7Rα induces lymphoid leukemia as well as myeloproliferative disease. In vivo oncogenicity of mutant IL7Rα is influenced by the differentiation stage at which it occurs.

Cited by 31 publications

References 27 publications

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity

An instructive role for IL7RA in the development of human B-cell precursor leukemia

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