IL7R mutation

Patients with IL7R mutations have higher NRM, shorter OS, and EFS than patients without IL7R mutations, even patients who have undergone HSCT. Future larger and multicentric prospective studies will be explored.

We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.

P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026

Overall, our studies demonstrate that SKs are key players in oncogenic, but not in physiological, IL-7/IL-7R-mediated signaling. We uncover the importance of the SK-IL7R signaling crosstalk in ALL and pinpoint the therapeutic potential of SK inhibitors for IL-7R-dependent ALL.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Altogether, this study provides valuable information to optimize translation of JAKi and venetoclax to clinics for T-ALL patients with relapse who need therapeutics to bridge to transplant. This treatment protocol may benefit to a larger group of patients who may be selected with an easily applicable flow-cytometry-based companion test. IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T- ALL patients eligible to JAKi up to nearly ~70% of T-ALL.

P1, N=15, Recruiting, University of Chicago | Trial primary completion date: Sep 2022 --> Sep 2023

Conversely, mutants were more sensitive to venetoclax than expressers. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

In fact, ADCP levels induced by OSE-127 treatment in vitro correlated with its capacity to reduce ALL blasts in the blood of PDX mice in vivo. Altogether, through its dual mode of action, OSE-127 may represent a powerful novel immunotherapy option for ALL patients, including cases with dysregulated IL7R signaling, particularly in combination with standard of care polychemotherapy.

P1/2, N=26, Not yet recruiting, Princess Maxima Center for Pediatric Oncology

P2, N=171, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting

P2, N=170, Recruiting, Incyte Corporation | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Dec 2024 --> Sep 2025

Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.

A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids' mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.

P2, N=170, Recruiting, Incyte Corporation | Trial primary completion date: Feb 2024 --> Dec 2024

CRISPR mediated gene silencing of CDKN2A in primary human CD34 cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

These comprehensive studies point to a hitherto unexplored significant role of the IL7R gene in ovarian carcinoma. It is envisaged that the work will lay the foundation for the development of a novel biomarker with potential application in molecular profiling and in estimation of the disease prognosis.Communicated by Ramaswamy H. Sarma.

P2, N=170, Recruiting, Incyte Corporation | Trial completion date: May 2024 --> Dec 2024

Because IL7R mutant leukemias exhibit clear upregulation of mTOR signaling, we administered the clinical-grade dual PI3K and mTOR inhibitor dactolisib and show it has a striking impact on the frequency of leukemia cells in the blood, significantly prolonging mouse survival...Importantly, we validated our findings in IL7R mutant primary human B-ALLs. Conclusion Our studies provide a novel, powerful in vivo resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, and demonstrate for the first time that IL7R can initiate this malignancy.

Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-in mice drives potential thymocyte self-renewal, and thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia...Notably, we also find that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and can progress in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling Ruxolitinib (Jak1), AZD1208 (Pim), Dactolisib (PI3K/mTOR), Palbociclib (Cdk4/6), and Venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.

Our results are confirmed by induction of a similar phenotype with a combination of overexpressed WT c-Myc and mutant IL7Rα, which caused severe leukemia as early as 16 days post-transplant. Taken together, we developed a robust model to study T-ALL in mice, shed light on novel pathways of oncogenesis and discovered new targets for intervention that could lead to better therapeutic development.

When we combine prednisolone treatment with selumetinib or ruxolitinib, we observe that ruxolitinib only synergizes with prednisolone in IL7-dependent steroid resistant PDX samples in the presence of IL7. Moreover, our data proposes that this synergistic effect may (in part) depend on the anti-MAPK-ERK effect downstream of JAK1/2-inhibition. Combined, our study strongly supports the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507), and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.

Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321).

IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

P1, N=15, Active, not recruiting, University of Chicago | Not yet recruiting --> Active, not recruiting