EGAGenomicsGianni Cazzanigahttps://ega-archive.org/dacs/EGAC00001000644EGAEGA DAC EGAC00001000644EGAgianni.cazzaniga@asst-monza.itChildren with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2^pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2^pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome.Schwartzman Omer O, Savino Angela Maria AM, Gombert Michael M, Palmi Chiara C, Cario Gunnar G, Schrappe Martin M, Eckert Cornelia C, von Stackelberg Arend A, Huang Jin-Yan JY, Hameiri-Grossman Michal M, Avigad Smadar S, Te Kronnie Geertruy G, Te Kronnie Geertruy G, Geron Ifat I, Birger Yehudit Y, Rein Avigail A, Zarfati Giulia G, Fischer Ute U, Mukamel Zohar Z, Stanulla Martin M, Biondi Andrea A, Cazzaniga Giovanni G, Vetere Amedeo A, Wagner Bridget K BK, Chen Zhu Z, Chen Sai-Juan SJ, Tanay Amos A, Borkhardt Arndt A, Izraeli Shai Sfbwd4, XX, XY, Childhood., Trisomy 21 NOS, l(2)04454, DmelCG1772, precursor lymphoblastic lymphoma/leukemia, CIB1, Lymphocytic Leukemia, G Trisomy, acute lymphoblastic leukaemia, p21[dacapo], cdi4, FBWD4, Cdi4, CDI4, Down's, Decapo, trisomy 21 syndrome, Childhood ALL, Down's syndrome - trisomy 21, Lymphocytic, Leukemia, lymphoblastic leukaemia, Partial Trisomy 21 Down Syndrome, shsf3, shfm3, E(Sev-CycE)2B, Fbw4, FBW4, Adult, Mongolism, L2 Lymphocytic, SHFM3, Acute Lymphoblastic, L1, lymphoblastic leukemia, trisomy 21, L2, Dac, DAC, L1 Lymphocytic, Meiotic Nondisjunction, dacapo/cyclin-dependent kinase interactor 4, Down syndrome, Precursor Cell Lymphoblastic Leukemia Lymphoma, AI182278, Syndrome, Dap, CES5A1, Acute lymphoblastic leukemia, Lymphoid, P15, fbw4, SHSF3, ALL, 47, dac, Trisomy 21, Down Syndrome, Down's Syndrome, Complete trisomy 21 syndrome, Lymphoid Leukemia, Philadelphia-Positive, dactylin, not genetically inherited, L1 Lymphocytic Leukemia, E130112M23Rik, Lymphoblastic Lymphoma, Down's syndrome NOS (disorder), Complete trisomy 21 syndrome (disorder), +21, Acute Lymphoid Leukemia, dactylyn, p21, CG1772, Acute Lymphocytic, p27, Acute Lymphoid, acute lymphocytic leukaemia, Lymphoblastic Leukemia, Trisomy 21 Syndrome, Down's syndrome NOS, Trisomy G, Lymphoblastic, complete trisomy 21 syndrome, Childhood, Acute Lymphoblastic Leukemia, Mitotic Nondisjunction, Dach, CDKN2B, Down, Acute, p27[Dap], Lymphoma, L2 Lymphocytic Leukemia, T21 - Trisomy 21, Acute Lymphocytic Leukemia, Partial Trisomy 21, Downs SyndromeXX, XY, Trisomy 21 NOS, Antemortem Diagnosis, precursor lymphoblastic lymphoma/leukemia, Hop1, Lymphocytic Leukemia, G Trisomy, jak, acute lymphoblastic leukaemia, Diagnosis, relapse, HOP, Hop, l(1)L4, Mass, symptoms, Screening, Down's, 4, Relapses, Antemortem, Childhood ALL, trisomy 21 syndrome, Lymphocytic, DmelCG1594, Tum-1, Leukemia, lymphoblastic leukaemia, Partial Trisomy 21 Down Syndrome, Recrudescences, Recurrences, Diagnoses and Examinations, Adult, l(1)hop, Mongolism, L2 Lymphocytic, Acute Lymphoblastic, L1, lymphoblastic leukemia, L2, trisomy 21, L1 Lymphocytic, L4, Meiotic Nondisjunction, Down syndrome, Precursor Cell Lymphoblastic Leukemia Lymphoma, Janus kinase activity, Syndrome, Acute lymphoblastic leukemia, Lymphoid, Diagnose, single organism signaling, ALL, Antemortem Diagnoses, screening, Relapse, 47, findings, Trisomy 21, Down Syndrome, Down's Syndrome, Lymphoid Leukemia, Philadelphia-Positive, Complete trisomy 21 syndrome, L1 Lymphocytic Leukemia, Examination and Diagnoses, Diagnoses, Lymphoblastic Lymphoma, Postmortem, Screenings, Down's syndrome NOS (disorder), Recrudescence, Acute Lymphoid Leukemia, Complete trisomy 21 syndrome (disorder), +21, Mass Screenings, Examinations and Diagnoses, Acute Lymphocytic, Acute Lymphoid, Postmortem Diagnosis, acute lymphocytic leukaemia, d-jak, Lymphoblastic Leukemia, Diagnoses and Examination, DmHD-160, Postmortem Diagnoses, Trisomy 21 Syndrome, Down's syndrome NOS, Down's syndrome - trisomy 21., Trisomy G, Lymphoblastic, signs, complete trisomy 21 syndrome, Childhood, Acute Lymphoblastic Leukemia, Mitotic Nondisjunction, Down, Dm JAK, Acute, signalling process, HD-160, Tum, Lymphoma, msvl, l(1)G18, L2 Lymphocytic Leukemia, T21 - Trisomy 21, JAK, Jak, CG1594, l(1)10Be, Acute Lymphocytic Leukemia, Partial Trisomy 21, Downs SyndromeAI504024, Ras1/RAs85D, Trisomy 21 NOS, RAS, Ras, B Cells, Antemortem Diagnosis, l(1)G0098, single-organism developmental process, determination, acetylglucosaminyltransferase-like protein, Pre B ALL, Bursa-Dependent Lymphocytes, FON1, postnatal development, FAF-X, B cell, positive regulation by symbiont of host non-apoptotic programmed cell death, Mbp1, c-rasHa, jak, E(sev)3C, growth and development, Ras-1, FLORAL ORGAN NUMBER 1, JTK10, Diagnosis, TSLP Cytokine, CG11485, Pre-B ALL, Mutations, Relative, relapse, ras, c-ras2, HOP, Hop, l(1)L4, SUP, symptoms, Alleviating interaction, pathogenesis, 4, Relapses, Stromal Lymphopoietin, Fs(3)Hor, myd, D-Ras1, treatment, DmelCG1594, Pre-B-Cell, Pre-B-Cell Leukemia, increased, pre-B-cell, DmelCG2684, ubiquitin hydrolase activity, me75, Precursor B-Cell Lymphoblastic Leukemia, Tum-1, RTK, stimulation by symbiont of host programmed cell death, like-acetylglucosaminyltransferase, Recurrences, l(1)G0436, Pre B Cell, Bdr, Mbp-1, ras85B, ras85D, NTef2, Super protein, ubiquitin C-terminal hydrolase, D17Mit170, sp, T1, SNAP-25, genetic, AA407302, TSLP, trisomy 21, D-ras-2, B lymphocyte, Meiotic Nondisjunction, Janus kinase activity, disease management, Therapies, Diagnose, single organism signaling, CG1799, ubiquitin C-terminal hydrolase activity, Diagnostic Findings, Deubiquitinating, Therapy, screening, Relapse, SIGNS SYMPTOMS, 47, l(3)s1747, Precursor B Cell Lymphoblastic Leukemia, Ras2, RAS2, Thymic, Ras1, RAS1, gyltl1b-b, B Lymphocytes, Ki-ras, DESC, Trisomy 21, familial, Down's Syndrome, DFFRX, Tl3, Tl2, JAK2, Pre B Cell Leukemia, Diagnoses, Fs(3)Sz11, THCYT3, Dffrx, B cell precursor, Down's syndrome NOS (disorder), Postmortem, Screenings, JAK-2, Recrudescence, MDDGA6, Examinations and Diagnoses, mKIAA0609, Relative Risks, dRas85D, modulation by symbiont of host system process, GENA70, p21[Ras1], dRas1, dRAS1, Postmortem Diagnosis, ras1, KIAA0609, Dras85D, ras2, d-jak, acetylglucosaminyltransferase-like 1A, ras-2, BcDNA:RE36103, AA407699, Fafl, Diagnoses and Examination, fg, Postmortem Diagnoses, DmHD-160, l(1)G0351, LD02673, gyltl1b, Trisomy 21 Syndrome, Risk, death rate, Down's syndrome NOS, DmelCG1799, c-Ha-ras, Deubiquitinases, D-ras1, l(1)G0238, D-ras2, Precursor B Cell Lymphoblastic Leukemia Lymphoma, Hras-1, mdc1d, signs, C-ras1, Dm Ras1, Dras64B, Mitotic Nondisjunction, Children, LARGE_HUMAN, C-ras2, Treatments, early, l(3)06677, Precursor B-Cell Lymphoblastic Lymphoma, l(1)G0002, Down, RasI, MDC1D, metastatic, l(1)G0482, enr, HD-160, c-H-ras, FAF, B-Lymphocyte, Horka, activation by symbiont of host programmed cell death, l(1)G0127, msvl, CG2684, Fs(3)Horka, FAM, inherited genetic, CG1594, Clinical Finding, Harvey-ras, Partial Trisomy 21, accessory, Hras1, FLORAL DEFECTIVE 10, XX, XY, Hop1, RasV12, G Trisomy, regulation by symbiont of host system process, dRas, ubiquitinyl hydrolase 1 activity, Kras2, CG1167, H-ras, DRAS1, DRas2, Janus kinase 2, SUPERMAN, Deubiquitinating Enzyme, DmelCG9375, IMPDH, supernumerary, LARGE1, LD06825, deubiquitylase, froggy, Symptoms and Signs, Gyltl1a, Dras2, Dras1, l(1)G0388, deubiquitinase activity, D-Ras, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, Mass, Screening, Kras-2, AL022749, C81284, Down's, DmF2, Low, Antemortem, Finding, IMPdH, Ha-ras, l(1)G0380, trisomy 21 syndrome, Down's syndrome - trisomy 21, lod, Dras, p21B, ras 1, B-cell, RGD1560056, Leukemia, dras1, Dm-ras-64B, Pre B-ALL, Partial Trisomy 21 Down Syndrome, Recrudescences, raspberry/impd, MDDGB6, LARGE, causes, Diagnoses and Examinations, Ras[V12], l(1)G0391, EK3-4, suppressive genetic interaction (sensu inequality), Mongolism, l(1)hop, DRas, DRas85D/Ras, Ras 85D, Dmras64B, UBP, BPFD#36, Mif1, Enzyme, L4, Down syndrome, time of survival, Syndrome, causality, Precursor B Cell Lymphoblastic Lymphoma, ras-l, constitutitional genetic, single organism signaling., disease remission, l(1)G0056, Antemortem Diagnoses, B-cell precursor, activation by organism of non-apoptotic programmed cell death in other organism, findings, cou, hemolysin activity, CG9375, Lymphopoietin, Down Syndrome, pre-B cell, AL022658, K-ras, Deubiquitinase, Complete trisomy 21 syndrome, Synaptosomal-associated 25 kDa protein, function, Thymic Stromal, D-ras-1, Examination and Diagnoses, Leukemias, Cell, E(faf), Enzymes, development, DmelCG1167, Signs and Symptoms, fs(3)05703, Fd17, Lr, Cytokine, survival, Complete trisomy 21 syndrome (disorder), +21, Mass Screenings, EP(X)1093, chemical analysis, S35097, AI929937, Relative Risk, RAS85D, Dmras85D, l(1)9Eb, increased number, Trisomy G, Risks, MRX99, postnatal growth, complete trisomy 21 syndrome, Bursa-Equivalent Lymphocyte, FLO10, Lds, HERP, Su(tor)3-2, UCH2, Pre-B-Cell Leukemias, present in greater numbers in organism, Dm JAK, deubiquitinating enzyme, signalling process, like-glycosyltransferase, Therapeutic, SNAP, Tum, deubiquitinase, Bra, l(1)G18, Treatment, T21 - Trisomy 21, assay, JAK, Jak, l(1)10Be, B-lymphocyte, growth, hereditary, Downs Syndrome, 5730589N07Rik, glycosyltransferase-like protein LARGE1falseDAC for data acquired during the Down Syndrome acute lymphoblastic leukemia project. The project was performed with clinical samples of the AIEOP-BFM trial.Data Access Committee EGAC00001000644

2025-1-9

EGAC00001000644960628461505EGAS00001002410EGAD00001003275EGAD00001003280