Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential

Treanor, Louise M.; Zhou, Sheng; Janke, Laura J.; Churchman, Michelle L.; Ma, Zhuo; Lu, Taihe; Chen, Shann-Ching; Mullighan, Charles G.; Sorrentino, Brian P.

doi:10.1084/jem.20122727

Cited by 91 publications

(97 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 In very recent work, ruxolitinib modestly prolonged survival in a model that phenotypically resembles ETP-ALL, in which IL7R mutants transformed murine thymocytes, inducing a leukemia with stem cell and myeloid features. 42 This work provides strong evidence that IL7R mutations are leukemogenic drivers; however, IL7R mutations have been identified in ,10% of ETP-ALL cases. As IL7R is known to drive JAK/STAT signaling, it is not surprising that targeting JAK/STAT was effective in that model.…”

Section: Discussionmentioning

confidence: 74%

Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

Maude

Dolai

Delgado-Martín

et al. 2015

Blood

Self Cite

192

176

View full text Add to dashboard Cite

• ETP-ALL, a high-risk subtype of T-ALL, is characterized by aberrant activation of the JAK/STAT signaling pathway.• The JAK1/2 inhibitor ruxolitinib demonstrates robust activity in patientderived xenograft models of ETP-ALL.Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P < .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P < .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed. (Blood. 2015;125(11):1759-1767 Introduction Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) was first described in 2009 as a subtype of T-ALL with a unique immunophenotype that includes expression of myeloid and early progenitor or stem cell markers in addition to T-cell lineage markers. 1Although overall survival for the majority of T-ALL cases has improved dramatically over the last 50 years, 2 largely due to intensification of chemotherapy regimens, many published studies suggest a large percentage of ETP-ALL cases have dismal outcomes.1,3-7 More recent studies suggest that children with ETP-ALL treated on contemporary protocols that intensify therapy based on minimal residual disease response may not fare as poorly as originally thought. 8,9 ETP-ALL, which represents ;10% to 15% of new T-ALL diagnoses in children 1,4,5 and ;10% to 30% in adults, 3,6 accounts for a disproportionate fraction of T-ALL induction failures (ie, failure to achieve a morphologic remission at the end of the first month of chemotherapy). Novel therapies with alternative mechanistic approaches are urgently needed for chemotherapy-refractory subgroups of ETP-ALL.In addition to an immunophenotype with myeloid/stem cell markers, ETP-ALL cases demonstrate a similar transcriptional and mutational landscape to myeloid leukemias and hematopoietic stem ce...

show abstract

Section: Discussionmentioning

confidence: 74%

Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

Maude

Dolai

Delgado-Martín

et al. 2015

Blood

Self Cite

192

176

View full text Add to dashboard Cite

show abstract

“…on May 10, 2018. by guest www.bloodjournal.org From and PRC2 pathways in ETP ALL suggests that JAK inhibition and/or chromatin-modifying agents may be therapeutically useful. 49,50,74 Recent studies have provided additional insights into the biology of T-ALL. Exome sequencing identified recurrent mutations in ribosomal proteins and CNOT3, which encodes part of a transcriptional regulatory complex.…”

Section: 66mentioning

confidence: 99%

“…13,48,49 These mutations are often in the transmembrane domain and cause constitutive JAK-STAT signaling that may be abrogated with JAK inhibitors. 13,50 A minority of Ph-like cases have mutations activating Ras signaling (NRAS, KRAS, PTPN11, and NF1), 22 although these are not exclusively observed in Ph-like ALL. Several kinases are infrequently rearranged in Ph-like ALL, including NTRK3 and TYK2.…”

mentioning

confidence: 99%

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Hunger

Mullighan

2015

Blood

Self Cite

243

198

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. (Blood. 2015;125(26):3977-3987)

show abstract

“…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).…”

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

View full text Add to dashboard Cite

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.

show abstract

Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential

Abstract: Two interleukin-7 receptor mutants identified in human early T cell precursor leukemia are sufficient to induce disease in mice when expressed in primitive, Arf-null thymocytes.

Cited by 91 publications

References 37 publications

Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

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

Contact Info

Product

Resources

About