EGAGenomicsCancer Genomicshttps://ega-archive.org/studies/EGAS00001007144EGAEGA study EGAS00001007144RNA-sequencing of T-cell Acute Lymphoblastic Leukemia (T-ALL)EGArestrictedhlb368, acute T cell lymphoblastic leukemia, T-cell leukemia, Hop1, Il-7, T-cell acute lymphoblastic leukemia, Lymphopoietin 1, jak, T acute lymphoblastic leukemia, acute T-cell lymphocytic leukemia, T-cell type acute leukemia, precursor T-lymphoblastic lymphoma/leukemia, HOP, Hop, l(1)L4, sensitive, IL-7, T Acute Lymphoblastic Leukemia, acute T cell leukaemia, d-jak., acute T cell leukemia, 4, acute T-cell lymphoblastic leukemia, precursor T-lymphoblastic leukemia, sensitivity, acute T cell lymphocytic leukemia, T-ALL, T-cell acute lymphocytic leukaemia, DmelCG1594, T-cell acute lymphocytic leukemia, DmHD-160, A630026I06Rik, Tum-1, precursor T-lymphoblastic leukemia (T-cell ALL), frequent, T-cell ALL, Interleukin 7, Specificity, l(1)hop, allergic reaction, Lymphopoietin-1, Dm JAK, high frequency, L4, Specificity and Sensitivity, HD-160, acute T-cell leukemia, Tum, Janus kinase activity, T-cell lymphoblastic leukemia/lymphoma, msvl, Sensitivity, l(1)G18, Precursor T Lymphoblastic Leukemia, IL7, JAK, Jak, CG1594, l(1)10Behlb368, protein translation, acute T cell lymphoblastic leukemia, T-cell leukemia, INC424, Biological Markers, Viral Marker, Materials, Surrogate Endpoints, CDw127, determination, Laboratory, Heterograft, precursor T-cell acute lymphoblastic leukemia/lymphoma, Blood, Il-7, Biochemical, Endpoint, jak, acute T-cell lymphocytic leukemia, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2, TRANSPL HETEROL, 3-b)pyridin-5-yloxy)benzamide, Serum, Precursor T Cell Lymphoblastic Lymphoma, Acute., Mutations, Laboratory Markers, Acute T-Cell Leukemia, HOP, Hop, diseases, l(1)L4, Roles, IL-7RA, Biological, Associations, T-Lymphocytic Leukemia, IL-7, Concepts, diseases and disorders, 4, Precursor T Cell Lymphoblastic Leukemia, T-ALL, T-Lymphocytic Leukemias, DmelCG1594, T-cell acute lymphocytic leukemia, human disease, Tum-1, precursor T-lymphoblastic leukemia (T-cell ALL), Prognoses, T-cell ALL, Clinical Importance, Leucocythemias, Venclexta, CDW127, IL-7Ralpha, Epigenomic, ruxolitinib (as phosphate), genetic, INC-424, allergic reaction, high frequency, Immune, Xenotransplantations, Markers, Viral Markers, acute T-cell leukemia, Role Concepts, Janus kinase activity, Homo sapiens disease, Malignancies, precursor T-cell acute lymphoblastic leukemia, Bridge-1, protein anabolism, 4-dimethyl-1-cyclohexen-1-yl)methyl)-1-piperazinyl)-n-((3-nitro-4-(((tetrahydro-2h-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(1h-pyrrolo(2, protein biosynthetic process, Viral, Surrogate Endpoint, Acute T-Cell Leukemias, IL7RA, familial, Biochemical Markers, Biologic Marker, Significance, 3-d)pyrimidin-4-yl)pyrazol-1-yl)propanenitrile, mislocalized, Role Concept, T-Cell, Playthings and Play, Marker, Diseases, Accomplishments, Role, ILRA, protein formation, Plaything, Hematopoietic Malignancies, Genetic Materials, acute T cell leukaemia, acute T cell leukemia, precursor T-lymphoblastic leukemia, Heterologous Transplantations, Genetic Material, d-jak, Bridge, Lymphoblastic Leukemia, T-cell acute lymphocytic leukaemia, Xenograft, RG-7601, Hematopoietic, Leucocythemia, DmHD-160, T Cell Leukemia, Xenotransplantation, Acute T-Lymphocytic Leukemias, Factors, GDC-0199, INCB018424, death rate, End Points, Transplantation, Epigenetic, Prognostic, INCB018424 phosphate, Relevance, Toys, 4-(4-((2-(4-chlorophenyl)-4, precursor T-cell acute lymphocytic leukemia/lymphoma, Hematologic Malignancies, Xenografts, Immunologic, Acute T-Lymphocytic Leukemia, 3-b)pyridin-5-yloxy)-, Laboratory Marker, precursor T-cell acute lymphocytic leukemia, disease, antagonists and inhibitors, Specificity and Sensitivity, Patient, protein synthesis, Material, HD-160, Biochemical Marker, msvl, Hematologic Neoplasm, Cistron, T Cell, inherited genetic, CG1594, Epigenetics, Prognostic Factor, ruxolitinib monophosphate, other disease, Plays, opzelura, IL-7R-alpha, Lymphocytic Leukemia, Hop1, ectopic, Clinical Markers, Clinical Marker, Neoplasms, Importance, Gene, Prognostic Factors, Transplantations, T-Cell Leukemias, heterologous transplantation, Surrogate End Points, precursor T-lymphoblastic lymphoma/leukemia, Surrogate Markers, Hematopoietic Neoplasm, INCB-018424 phosphate, T-Cell Acute Lymphocytic Leukemia, Hematopoietic Malignancy, sensitive, Blood Cancers, T Acute Lymphoblastic Leukemia, leukaemia NOS, disease or disorder, Precursor T-Cell Lymphoblastic Leukemia, Leucocythaemia, acute T-cell lymphoblastic leukemia, Clinical Significance, leukaemia, INCA24, RG7601, sensitivity, Hematological Malignancy, INCB-18424 phosphate, Toy, Lymphocytic, Biomarker, Leukemia, Genetic, Clinical, Malignancy, Playthings, 3R)-3-cyclopentyl-3-(4-(7H-pyrrolo(2, Precursor T-Cell Lymphoblastic Lymphoma, Biological Marker, Interleukin 7, inhibiteur, Heterografts, Hematopoietic Neoplasms, l(1)hop, ABT-199, non-neoplastic, Lymphopoietin-1, Hematological Neoplasms, Immunologic Markers, Acute T-Lymphocytic, Hematologic Malignancy, Puppets, inhibidor, L4, time of survival, Clients, T-cell lymphoblastic leukemia/lymphoma, Play, disorder, Sensitivity, IL7, ruxolitinib phosphate, Acute T-Cell, constitutitional genetic, IL-7R subunit alpha, Immunologic Marker, IL7R, Puppet, Heterologous, Biologic, Cancer, disease remission, Hematological Malignancies, leukemia, inhibitors, INCB-18424, T-cell acute lymphoblastic leukemia, Serum Markers, Hematologic, disorders, Lymphopoietin 1, End Point, inhibitor, T acute lymphoblastic leukemia, Factor, medical condition, T-cell type acute leukemia, Hematological Neoplasm, Cistrons, Client, Leukemias, T-Cell Leukemia, Immune Marker, Concept, benzamide, XENOTRANSPL, survival, IL-7 receptor subunit alpha, Surrogate End Point, chemical analysis, Jakavi, Neoplasm, condition, protein biosynthesis, Achievements, acute T cell lymphocytic leukemia, Acute T Cell, Leucocythaemias, Jakafi, Biologic Markers, antagonists, A630026I06Rik, Serum Marker, frequent, Surrogate, Blood Cancer, Endpoints, Lymphoblastic, Specificity, INCB-018424, HETEROL TRANSPL, Surrogate Marker, T Lymphocytic Leukemia, INCB-018424 salt, Dm JAK, Accomplishment, Acute, Precursor T Cell Lymphoblastic Leukemia Lymphoma, Hematological, Tum, l(1)G18, Precursor T Lymphoblastic Leukemia, JAK, Jak, assay, l(1)10Be, CD127, hereditary, Immune MarkersfalseIL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibitionT-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. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. 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.2023-04-11 15:36:50EGAS000010071449606EGAD00001010273EGAC00001003183