Cell Collective7024000ModelsShannyn Birdhttps://cellcollective.org/#4942/proinflammatory-tumor-microenvironment-in-acute-lymphoblastic-leukemia14.48071SBML1Cell Collectivehttps://cellcollective.org/#4942:1/proinflammatory-tumor-microenvironment-in-acute-lymphoblastic-leukemiaLineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the BM. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status. Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-κB induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells.Modeling the Pro-inflammatory Tumor Microenvironment in Acute Lymphoblastic Leukemia Predicts a Breakdown of Hematopoietic-Mesenchymal Communication Networks.Enciso Jennifer J, Mayani Hector H, Mendoza Luis L, Pelayo Rosana Rl(3)rK137, tollo, stromal cell-derived factor-1 receptor activity, determination, CG5490, Stem Cells, Stromal Cells, Cue, Mesenchymal Stromal Cells, dToll, Multipotent Mesenchymal Stromal Cell, Scyb12, tehao, Tl-4, congenital defects, Medullary, Tl-3, Tumor, sdf-1, EP1051, CG17228, aplasia, temporal, 1135/09, Medullary Hematopoiesis, 18w-like, hsy3rr, 1135/07, DmMstProx, Personal, Communications, LAP-3, medulla ossea, symptoms, 0451/09, Scanning Transmission Electron Microscopy, Miscommunication, ARMD10, CT22017, Tumor Microenvironments, primary stem, mesenchymal precursor cell, lestr, CD106, LAP3, IKKg, KEY, Key, IRH, Multipotent Mesenchymal Stromal Cells, average, SCYB12, SDF-1 receptor activity, 0244/09, 18-w, MUB3_18, FATE, Personnel, DROPROSA, hypoplasia, mesenchymal, Bone Marrow Stromal Stem Cells, Social Communications, MUB3.18, l(3)j6E2, CFU-F, Tho, T1, toll-1, Red Marrow, Communication, Social, 671/2, Bone Marrow Mesenchymal Stem Cells, 0320/10, Tl-8, Tl-7, DmelCG8896, toll-6, DMPROSPER, Tl-6, Tl-5, blood cell formation, npyr, Whartons Jelly Cells, marrow stromal cells, Red, xSDF-1, CT22359, tl, TL, 18-wheeler, single organism signaling, NPYR, Cancer Microenvironments, screening, l(3)rO534, aberrant, Social Communication, PRO, Pro, CT25100, Mesenchymal Progenitor Cells, Hematopoiesis, npyy3r, DmelCG5490, SDF1, Adipose Tissue-Derived Mesenchymal Stem Cell, Sdf1, CYS, deformities, Programs, Electron Microscopy, Program, DmIKKgamma, PROS-1, Mesenchymal Stromal Cell, PROS-2, dTLR6, colony-forming unit-fibroblast, Stem Cell, sdf1, dTLR7, tollo/toll-8, dTLR8, dIKK, CG7121, pro, 1316/02, CT43, Kenny, BcDNA:HL08040, MscS, Ligature, PB-CKR, and GLY protein 2, cxcr4, activation, TL4, parent ion, atresia, TLR-4, Adipose-Derived, and GLY protein 1, acute lymphoblastic leukemia (ALL), Adipose-Derived Mesenchymal Stem Cells, mesenchymal stromal cells, CXCR4, Voila, CXCR7, Adipose Tissue Derived Mesenchymal Stromal Cells, medulla of bone, Tlsf, 0664/07, Tpar1, malformations, IKK-gamma, 1167/13, signs, CG8896, Adipose Tissue Derived Mesenchymal Stem Cells, mat(3)9, TAF[[II]], experimental procedures, Adipose-Derived Mesenchymal Stromal Cells, Adipose Derived, mesenchymal stem cell, TPAR1, Toll1, DmelCG16910, HM89, precursor ion, primary axis, Mesenchymal Progenitor Cell, TLSF, CT29238, anomalies, STEM, Mesenchymal, Adipose Derived Mesenchymal Stromal Cells, CG18241, Adipose Tissue Derived Mesenchymal Stem Cell, l(1)16Fg, Communication Program, hm89, Feedbacks, Bone Marrow Stromal Cells, 0989/01, Bone, tlr, pds, Misinformation, Multipotent Bone Marrow Stromal Cells, atypia, Mesenchymal Stem Cell, xCXCR4, experimental, Microenvironment, toll, Mesenchymal Stem Cells, 18W, Progenitor Cell, Adipose Tissue Derived Mesenchymal Stromal Cell, Toll 6, stalk, Wharton's Jelly Cells, cyclic nucleotide-regulated small mechanosensitive ion channel, Toll 5, precursor, haemopoiesis, 0763/13, TOLL, dIKK-gamma, l(3)10419, bone marrow stromal cells, dToll7, stem cells, NPYRL, dToll8, mstprox, dmTAF8, CD184, DmelCG17228, mel(3)9, dToll1, Cancer Microenvironment, Stromal Cell, dToll3, Marrow, DmIKK-gamma, dToll4, dToll5, HL-VIII, dToll6, TOL, anon-WO0140519.15, F15E12.6, npyrl, Cell., Misinformations, Wharton Jelly Cells, D2S201E, Yellow, atypical, dmIKKgamma, Prosp, defects, IKK[[gamma]], Wharton's Jelly Cell, mesenchymal stromal cell, DmelCG6890, CXCR-4-A, CXCR-4-B, PROS, Adipose Tissue-Derived Mesenchymal Stromal Cells, F15E12_6, Adipose Derived Mesenchymal Stem Cells, TOLL 6, methods, 0585/13, TOLL 7, TOLL 8, EP(3)1051, lymphoblastic leukaemia, CG7250, experimental section, cd184, Lps, CXC-R4-B, CG7128, CXC-R4-A, mesenchymal progenitor cells, dTLR3, dTLR4, dTLR5, CT24947, Maintenances, MSC, culm, CG1149, l(3)rH013, Ligations, Communication Programs, CD284, prod, lymphoblastic leukemia, Prodos, IKK, CG8595, Fs(1)Tl, TAF, 0563/18, Bone Marrow Mesenchymal Stem Cell, Adipose Derived Mesenchymal Stem Cell, Vcam-1, incidence, 0671/02, Cancer, Personal Communication, l(3)j12C8, lcr1, Adipose-Derived Mesenchymal Stem Cell, mel(3)10, findings, axis, l(2)00053, DmelCG18241, Progenitor Cells, INCAM-100, npy3r, function, Scanning Transmission, defective, Toll-1, Cell, WHIM, l(3)rJ806, Pros, CXCL12 receptor activity, IKKgamma, l(3)rL433, l(3)rI160, medulla ossium, 0441/16, agenesis, Communications Personnel, chemical analysis, TFIID, SDF1A, Fs(3)Tl, LESTR, SDF1B, DmelCG8595, ATCMPG1, MET, ATCMPG2, Pbsf, Yellow Marrow, Bone Marrow Stromal Cell, BMSC, CT17414, Ligatures, lap3, NPYY3R, medullary bone, Dmikkgamma, hematopoiesis, Multipotent Bone Marrow Stromal Cell, HSY3RR, fb22, Adipose Tissue-Derived Mesenchymal Stromal Cell, Haematopoiesis, DmelCG7250, CG16910, PBSF/SDF-1, FB22, Miscommunications, l(3)rK204, PBSF, Toll-8, Cmkar4, Toll-3, Adipose Tissue-Derived Mesenchymal Stem Cells, Toll-2, NPY3R, Toll-5, DmelCG7128, xcxcr4, signalling process, DmelCG1149, CG6890, birth defects, Multipotent, blood cell biosynthesis, CT21344, acute lymphoblastic leukaemia (ALL), assay, LCR1, Sdf1r, TAF8, Microenvironments, DmelCG7121l(3)rK137, single-organism catabolic process, multicellular organismal catabolic process, Misinformation, precursor lymphoblastic lymphoma/leukemia, Lymphocytic Leukemia, Microenvironment, acute lymphoblastic leukaemia, Tumor, 0763/13, CG17228, cellular catabolism, l(3)10419, 1135/09, 1135/07, dmTAF8, Personal, DmelCG17228, Communications, Cancer Microenvironment, HL-VIII, 0451/09, anon-WO0140519.15, cellular degradation, F15E12.6, Misinformations, Miscommunication, Prosp, Tumor Microenvironments, Childhood ALL, Lymphocytic, PROS, F15E12_6, 0244/09, 0585/13, Leukemia, lymphoblastic leukaemia, MUB3_18, breakdown of chemical, catabolism, Personnel, DROPROSA, CG7128, Social Communications, MUB3.18, l(3)j6E2, Adult, Communication, l(3)rH013, Social, 671/2, Communication Programs, prod, L2 Lymphocytic, 0320/10, Acute Lymphoblastic, Prodos, L1, lymphoblastic leukemia, DMPROSPER, L2, L1 Lymphocytic, Precursor Cell Lymphoblastic Leukemia Lymphoma, Acute lymphoblastic leukemia, Lymphoid, TAF, 0563/18, 0671/02, Cancer, Cancer Microenvironments, Personal Communication, l(3)j12C8, ALL, cellular breakdown, l(3)rO534, degradation, Social Communication, PRO, Pro, Lymphoid Leukemia, Philadelphia-Positive, CYS, L1 Lymphocytic Leukemia, l(3)rJ806, Pros, Programs, Lymphoblastic Lymphoma, Program, l(3)rL433, PROS-1, PROS-2, l(3)rI160, 0441/16, Acute Lymphoid Leukemia, pro, 1316/02, Communications Personnel, TFIID, BcDNA:HL08040, Acute Lymphocytic, Acute Lymphoid, acute lymphocytic leukaemia, and GLY protein 2, ATCMPG1, MET, ATCMPG2, breakdown of molecule, Lymphoblastic Leukemia, and GLY protein 1, breakdown, Voila, 0664/07, 1167/13, Lymphoblastic, Childhood, Acute Lymphoblastic Leukemia, TAF[[II]], Miscommunications, l(3)rK204, breakdown of substance, Acute, DmelCG7128, Lymphoma, Social., L2 Lymphocytic Leukemia, l(1)16Fg, Communication Program, TAF8, 0989/01, Microenvironments, Acute Lymphocytic Leukemia, pdsl(3)rK137, Childhood., precursor lymphoblastic lymphoma/leukemia, Lymphocytic Leukemia, Microenvironment, acute lymphoblastic leukaemia, Tumor, 0763/13, CG17228, l(3)10419, 1135/09, 1135/07, dmTAF8, DmelCG17228, Cancer Microenvironment, HL-VIII, 0451/09, anon-WO0140519.15, F15E12.6, Prosp, Tumor Microenvironments, Childhood ALL, Lymphocytic, PROS, F15E12_6, 0244/09, 0585/13, Leukemia, lymphoblastic leukaemia, MUB3_18, DROPROSA, CG7128, MUB3.18, l(3)j6E2, Adult, l(3)rH013, 671/2, prod, L2 Lymphocytic, 0320/10, Acute Lymphoblastic, Prodos, L1, lymphoblastic leukemia, DMPROSPER, L2, L1 Lymphocytic, Precursor Cell Lymphoblastic Leukemia Lymphoma, Acute lymphoblastic leukemia, Lymphoid, TAF, 0563/18, 0671/02, Cancer, Cancer Microenvironments, l(3)j12C8, ALL, l(3)rO534, PRO, Pro, Lymphoid Leukemia, Philadelphia-Positive, CYS, L1 Lymphocytic Leukemia, l(3)rJ806, Pros, Lymphoblastic Lymphoma, l(3)rL433, PROS-1, PROS-2, l(3)rI160, 0441/16, Acute Lymphoid Leukemia, pro, 1316/02, TFIID, BcDNA:HL08040, Acute Lymphocytic, Acute Lymphoid, acute lymphocytic leukaemia, and GLY protein 2, ATCMPG1, MET, ATCMPG2, Lymphoblastic Leukemia, and GLY protein 1, Voila, 0664/07, 1167/13, Lymphoblastic, Childhood, Acute Lymphoblastic Leukemia, TAF[[II]], l(3)rK204, Acute, DmelCG7128, Lymphoma, L2 Lymphocytic Leukemia, l(1)16Fg, TAF8, 0989/01, Microenvironments, Acute Lymphocytic Leukemia, pdsl(3)rK137, tollo, stromal cell-derived factor-1 receptor activity, determination, CG5490, Stem Cells, Stromal Cells, Cue, Mesenchymal Stromal Cells, dToll, Multipotent Mesenchymal Stromal Cell, Scyb12, tehao, Tl-4, congenital defects, Medullary, Tl-3, Tumor, sdf-1, EP1051, CG17228, aplasia, temporal, 1135/09, Medullary Hematopoiesis, 18w-like, hsy3rr, 1135/07, DmMstProx, Personal, Communications, LAP-3, medulla ossea, symptoms, 0451/09, Scanning Transmission Electron Microscopy, Miscommunication, ARMD10, CT22017, Tumor Microenvironments, primary stem, mesenchymal precursor cell, lestr, CD106, LAP3, IKKg, KEY, Key, IRH, Multipotent Mesenchymal Stromal Cells, average, SCYB12, SDF-1 receptor activity, 0244/09, 18-w, MUB3_18, FATE, Personnel, DROPROSA, hypoplasia, mesenchymal, Bone Marrow Stromal Stem Cells, Social Communications, MUB3.18, l(3)j6E2, CFU-F, Tho, T1, toll-1, Red Marrow, Communication, Social, 671/2, Bone Marrow Mesenchymal Stem Cells, 0320/10, Tl-8, Tl-7, DmelCG8896, toll-6, DMPROSPER, Tl-6, Tl-5, blood cell formation, npyr, Whartons Jelly Cells, marrow stromal cells, Red, xSDF-1, CT22359, tl, TL, 18-wheeler, single organism signaling, NPYR, Cancer Microenvironments, screening, l(3)rO534, aberrant, Social Communication, PRO, Pro, CT25100, Mesenchymal Progenitor Cells, Hematopoiesis, npyy3r, DmelCG5490, SDF1, Adipose Tissue-Derived Mesenchymal Stem Cell, Sdf1, CYS, deformities, Programs, Electron Microscopy, Program, DmIKKgamma, PROS-1, Mesenchymal Stromal Cell, PROS-2, dTLR6, colony-forming unit-fibroblast, Stem Cell, sdf1, dTLR7, tollo/toll-8, dTLR8, dIKK, CG7121, pro, 1316/02, CT43, Kenny, BcDNA:HL08040, MscS, Ligature, PB-CKR, and GLY protein 2, cxcr4, activation, TL4, parent ion, atresia, TLR-4, Adipose-Derived, and GLY protein 1, acute lymphoblastic leukemia (ALL), Adipose-Derived Mesenchymal Stem Cells, mesenchymal stromal cells, CXCR4, Voila, CXCR7, Adipose Tissue Derived Mesenchymal Stromal Cells, medulla of bone, Tlsf, 0664/07, Tpar1, malformations, IKK-gamma, 1167/13, signs, CG8896, Adipose Tissue Derived Mesenchymal Stem Cells, mat(3)9, TAF[[II]], experimental procedures, Adipose-Derived Mesenchymal Stromal Cells, Adipose Derived, mesenchymal stem cell, TPAR1, Toll1, DmelCG16910, HM89, precursor ion, primary axis, Mesenchymal Progenitor Cell, TLSF, CT29238, anomalies, STEM, Mesenchymal, Adipose Derived Mesenchymal Stromal Cells, CG18241, Adipose Tissue Derived Mesenchymal Stem Cell, l(1)16Fg, Communication Program, hm89, Feedbacks, Bone Marrow Stromal Cells, 0989/01, Bone, tlr, pds, Misinformation, Multipotent Bone Marrow Stromal Cells, atypia, Mesenchymal Stem Cell, xCXCR4, experimental, Microenvironment, toll, Mesenchymal Stem Cells, 18W, Progenitor Cell, Adipose Tissue Derived Mesenchymal Stromal Cell, Toll 6, stalk, Wharton's Jelly Cells, cyclic nucleotide-regulated small mechanosensitive ion channel, Toll 5, precursor, haemopoiesis, 0763/13, TOLL, dIKK-gamma, l(3)10419, bone marrow stromal cells, dToll7, stem cells, NPYRL, dToll8, mstprox, dmTAF8, CD184, DmelCG17228, mel(3)9, dToll1, Cancer Microenvironment, Stromal Cell, dToll3, Marrow, DmIKK-gamma, dToll4, dToll5, HL-VIII, dToll6, TOL, anon-WO0140519.15, F15E12.6, npyrl, Cell., Misinformations, Wharton Jelly Cells, D2S201E, Yellow, atypical, dmIKKgamma, Prosp, defects, IKK[[gamma]], Wharton's Jelly Cell, mesenchymal stromal cell, DmelCG6890, CXCR-4-A, CXCR-4-B, PROS, Adipose Tissue-Derived Mesenchymal Stromal Cells, F15E12_6, Adipose Derived Mesenchymal Stem Cells, TOLL 6, methods, 0585/13, TOLL 7, TOLL 8, EP(3)1051, lymphoblastic leukaemia, CG7250, experimental section, cd184, Lps, CXC-R4-B, CG7128, CXC-R4-A, mesenchymal progenitor cells, dTLR3, dTLR4, dTLR5, CT24947, Maintenances, MSC, culm, CG1149, l(3)rH013, Ligations, Communication Programs, CD284, prod, lymphoblastic leukemia, Prodos, IKK, CG8595, Fs(1)Tl, TAF, 0563/18, Bone Marrow Mesenchymal Stem Cell, Adipose Derived Mesenchymal Stem Cell, Vcam-1, incidence, 0671/02, Cancer, Personal Communication, l(3)j12C8, lcr1, Adipose-Derived Mesenchymal Stem Cell, mel(3)10, findings, axis, l(2)00053, DmelCG18241, Progenitor Cells, INCAM-100, npy3r, function, Scanning Transmission, defective, Toll-1, Cell, WHIM, l(3)rJ806, Pros, CXCL12 receptor activity, IKKgamma, l(3)rL433, l(3)rI160, medulla ossium, 0441/16, agenesis, Communications Personnel, chemical analysis, TFIID, SDF1A, Fs(3)Tl, LESTR, SDF1B, DmelCG8595, ATCMPG1, MET, ATCMPG2, Pbsf, Yellow Marrow, Bone Marrow Stromal Cell, BMSC, CT17414, Ligatures, lap3, NPYY3R, medullary bone, Dmikkgamma, hematopoiesis, Multipotent Bone Marrow Stromal Cell, HSY3RR, fb22, Adipose Tissue-Derived Mesenchymal Stromal Cell, Haematopoiesis, DmelCG7250, CG16910, PBSF/SDF-1, FB22, Miscommunications, l(3)rK204, PBSF, Toll-8, Cmkar4, Toll-3, Adipose Tissue-Derived Mesenchymal Stem Cells, Toll-2, NPY3R, Toll-5, DmelCG7128, xcxcr4, signalling process, DmelCG1149, CG6890, birth defects, Multipotent, blood cell biosynthesis, CT21344, acute lymphoblastic leukaemia (ALL), assay, LCR1, Sdf1r, TAF8, Microenvironments, DmelCG71217024falsePro-inflammatory Tumor Microenvironment in Acute Lymphoblastic LeukemiaLineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the BM. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status. Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-B induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells.2016-10-062017-03-312017-03-31494227594840