Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Targeting Immune Signaling Pathways in Clonal Hematopoiesis

Author(s): Nessar Ahmad Azrakhsh, Patrycja Mensah-glanowska, Kristoffer Sand and Astrid Olsnes Kittang*

Volume 26, Issue 28, 2019

Page: [5262 - 5277] Pages: 16

DOI: 10.2174/0929867326666190325100636

Price: $65

Abstract

Background: Myeloid neoplasms are a diverse group of malignant diseases with different entities and numerous patho-clinical features. They arise from mutated clones of hematopoietic stem- and progenitor cells which expand by outperforming their normal counterparts. The intracellular signaling profile of cancer cells is the sum of genetic, epigenetic and microenvironmental influences, and the multiple interconnections between different signaling pathways make pharmacological targeting complicated.

Objective: To present an overview of known somatic mutations in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and the inflammatory signaling pathways affected by them, as well as current efforts to therapeutically modulate this aberrant inflammatory signaling.

Methods: In this review, we extensively reviewed and compiled salient information with ClinicalTrials.gov as our source on ongoing studies, and PubMed as our authentic bibliographic source, using a focused review question.

Results: Mutations affecting immune signal transduction are present to varying extents in clonal myeloid diseases. While MPN are dominated by a few common mutations, a multitude of different genes can be mutated in MDS and AML. Mutations can also occur in asymptomatic persons, a finding called clonal hematopoiesis of indeterminate potential (CHIP). Mutations in FLT3, JAK, STAT, CBL and RAS can lead to aberrant immune signaling. Protein kinase inhibitors are entering the clinic and are extensively investigated in clinical trials in MPN, MDS and AML.

Conclusion: In summary, this article summarizes recent research on aberrant inflammatory signaling in clonal myeloid diseases and the clinical therapeutic potential of modulation of signal transduction and effector proteins in the affected pathways.

Keywords: Clonal hematopoiesis, MPN, MDS, MDS/MPN-RS-T, AML, inflammation, immune signaling pathways, targeting.

« Previous Next »
[1]
Steensma, D.P.; Bejar, R.; Jaiswal, S.; Lindsley, R.C.; Sekeres, M.A.; Hasserjian, R.P.; Ebert, B.L. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood, 2015, 126(1), 9-16.
[http://dx.doi.org/10.1182/blood-2015-03-631747] [PMID: 25931582]
[2]
Arber, D.A.; Orazi, A.; Hasserjian, R.; Thiele, J.; Borowitz, M.J.; Le Beau, M.M.; Bloomfield, C.D.; Cazzola, M.; Vardiman, J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 2016, 127(20), 2391-2405.
[http://dx.doi.org/10.1182/blood-2016-03-643544] [PMID: 27069254]
[3]
Leonard, J.P.; Martin, P.; Roboz, G.J. Practical Implications of the 2016 Revision of the World Health Organization Classification of Lymphoid and Myeloid Neoplasms and Acute Leukemia. Practical Implications of the 2016 Revision of the World Health Organization Classification of Lymphoid and Myeloid Neoplasms and Acute Leukemia. J. Clin. Oncol., 2017, 35(23), 2708-2715.
[http://dx.doi.org/10.1200/JCO.2017.72.6745] [PMID: 28654364]
[4]
Chereda, B.; Melo, J.V. Natural course and biology of CML. Ann. Hematol., 2015, 94(Suppl. 2), S107-S121.
[http://dx.doi.org/10.1007/s00277-015-2325-z] [PMID: 25814077]
[5]
Berk, P.D.; Goldberg, J.D.; Silverstein, M.N.; Weinfeld, A.; Donovan, P.B.; Ellis, J.T.; Landaw, S.A.; Laszlo, J.; Najean, Y.; Pisciotta, A.V.; Wasserman, L.R. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N. Engl. J. Med., 1981, 304(8), 441-447.
[http://dx.doi.org/10.1056/NEJM198102193040801] [PMID: 7005681]
[6]
Lundberg, P.; Karow, A.; Nienhold, R.; Looser, R.; Hao-Shen, H.; Nissen, I.; Girsberger, S.; Lehmann, T.; Passweg, J.; Stern, M.; Beisel, C.; Kralovics, R.; Skoda, R.C. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood, 2014, 123(14), 2220-2228.
[http://dx.doi.org/10.1182/blood-2013-11-537167] [PMID: 24478400]
[7]
Tefferi, A.; Vaidya, R.; Caramazza, D.; Finke, C.; Lasho, T.; Pardanani, A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J. Clin. Oncol., 2011, 29(10), 1356-1363.
[http://dx.doi.org/10.1200/JCO.2010.32.9490] [PMID: 21300928]
[8]
Cacemiro, M.D.C.; Cominal, J.G.; Tognon, R.; Nunes, N.S.; Simões, B.P.; Figueiredo-Pontes, L.L.; Catto, L.F.B.; Traina, F.; Souto, E.X.; Zambuzi, F.A.; Frantz, F.G.; Castro, F.A. Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation. Hematol Transfus Cell Ther, 2018, 40(2), 120-131.
[http://dx.doi.org/10.1016/j.htct.2017.12.003] [PMID: 30057985]
[9]
Zhang, J.; Fleischman, A.G.; Wodarz, D.; Komarova, N.L. Determining the role of inflammation in the selection of JAK2 mutant cells in myeloproliferative neoplasms. J. Theor. Biol., 2017, 425, 43-52.
[http://dx.doi.org/10.1016/j.jtbi.2017.05.012] [PMID: 28501635]
[10]
Hasselbalch, H.C. Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms. Expert Rev. Hematol., 2014, 7(2), 203-216.
[http://dx.doi.org/10.1586/17474086.2013.876356] [PMID: 24524202]
[11]
Schuler, E.; Schroeder, M.; Neukirchen, J.; Strupp, C.; Xicoy, B.; Kündgen, A.; Hildebrandt, B.; Haas, R.; Gattermann, N.; Germing, U. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk. Res., 2014, 38(12), 1413-1419.
[http://dx.doi.org/10.1016/j.leukres.2014.09.003] [PMID: 25444076]
[12]
Wang, S.A.; Hasserjian, R.P.; Fox, P.S.; Rogers, H.J.; Geyer, J.T.; Chabot-Richards, D.; Weinzierl, E.; Hatem, J.; Jaso, J.; Kanagal-Shamanna, R.; Stingo, F.C.; Patel, K.P.; Mehrotra, M.; Bueso-Ramos, C.; Young, K.H.; Dinardo, C.D.; Verstovsek, S.; Tiu, R.V.; Bagg, A.; Hsi, E.D.; Arber, D.A.; Foucar, K.; Luthra, R.; Orazi, A. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood, 2014, 123(17), 2645-2651.
[http://dx.doi.org/10.1182/blood-2014-02-553800] [PMID: 24627528]
[13]
Patnaik, M.M.; Tefferi, A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer J, 2016.6e393.
[http://dx.doi.org/10.1038/bcj.2016.5] [PMID: 26849014]
[14]
Padron, E.; Steensma, D.P. Cutting the cord from myelodysplastic syndromes: chronic myelomonocytic leukemia-specific biology and management strategies. Curr. Opin. Hematol., 2015, 22(2), 163-170.
[http://dx.doi.org/10.1097/MOH.0000000000000112] [PMID: 25575034]
[15]
Malcovati, L.; Papaemmanuil, E.; Bowen, D.T.; Boultwood, J.; Della Porta, M.G.; Pascutto, C.; Travaglino, E.; Groves, M.J.; Godfrey, A.L.; Ambaglio, I.; Gallì, A.; Da Vià, M.C.; Conte, S.; Tauro, S.; Keenan, N.; Hyslop, A.; Hinton, J.; Mudie, L.J.; Wainscoat, J.S.; Futreal, P.A.; Stratton, M.R.; Campbell, P.J.; Hellström-Lindberg, E.; Cazzola, M. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood, 2011, 118(24), 6239-6246.
[http://dx.doi.org/10.1182/blood-2011-09-377275] [PMID: 21998214]
[16]
Papaemmanuil, E.; Cazzola, M.; Boultwood, J.; Malcovati, L.; Vyas, P.; Bowen, D.; Pellagatti, A.; Wainscoat, J.S.; Hellstrom-Lindberg, E.; Gambacorti-Passerini, C.; Godfrey, A.L.; Rapado, I.; Cvejic, A.; Rance, R.; McGee, C.; Ellis, P.; Mudie, L.J.; Stephens, P.J.; McLaren, S.; Massie, C.E.; Tarpey, P.S.; Varela, I.; Nik-Zainal, S.; Davies, H.R.; Shlien, A.; Jones, D.; Raine, K.; Hinton, J.; Butler, A.P.; Teague, J.W.; Baxter, E.J.; Score, J.; Galli, A.; Della Porta, M.G.; Travaglino, E.; Groves, M.; Tauro, S.; Munshi, N.C.; Anderson, K.C.; El-Naggar, A.; Fischer, A.; Mustonen, V.; Warren, A.J.; Cross, N.C.; Green, A.R.; Futreal, P.A.; Stratton, M.R.; Campbell, P.J. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med., 2011, 365(15), 1384-1395.
[http://dx.doi.org/10.1056/NEJMoa1103283] [PMID: 21995386]
[17]
Niemeyer, C.M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi, A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.; Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van’t Veer-Korthof, E.T.; van Wering, E.; Zimmermann, M. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. Blood, 1997, 89(10), 3534-3543.
[PMID: 9160658]
[18]
Passmore, S.J.; Hann, I.M.; Stiller, C.A.; Ramani, P.; Swansbury, G.J.; Gibbons, B.; Reeves, B.R.; Chessells, J.M. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood, 1995, 85(7), 1742-1750.
[PMID: 7703482]
[19]
Locatelli, F.; Nöllke, P.; Zecca, M.; Korthof, E.; Lanino, E.; Peters, C.; Pession, A.; Kabisch, H.; Uderzo, C.; Bonfim, C.S.; Bader, P.; Dilloo, D.; Stary, J.; Fischer, A.; Révész, T.; Führer, M.; Hasle, H.; Trebo, M.; van den Heuvel-Eibrink, M.M.; Fenu, S.; Strahm, B.; Giorgiani, G.; Bonora, M.R.; Duffner, U.; Niemeyer, C.M. European Working Group on Childhood MDS; European Blood and Marrow Transplantation Group. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood, 2005, 105(1), 410-419.
[http://dx.doi.org/10.1182/blood-2004-05-1944] [PMID: 15353481]
[20]
Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute Myeloid Leukemia. N. Engl. J. Med., 2015, 373(12), 1136-1152.
[http://dx.doi.org/10.1056/NEJMra1406184] [PMID: 26376137]
[21]
Bennett, J.M. Changes in the Updated 2016: WHO Classification of the Myelodysplastic Syndromes and Related Myeloid Neoplasms. Clin. Lymphoma Myeloma Leuk., 2016, 16(11), 607-609.
[http://dx.doi.org/10.1016/j.clml.2016.08.005] [PMID: 27693133]
[22]
Infante, M.S.; Piris, M.A.; Hernandez-Rivas, J.A. Molecular alterations in acute myeloid leukemia and their clinical and therapeutical implications. Med. Clin. (Barc.), 2018, 151(9), 362-367.
[http://dx.doi.org/10.1016/j.medcle.2018.05.002] [PMID: 29895422]
[23]
Abrahamson, G.; Boultwood, J.; Madden, J.; Kelly, S.; Oscier, D.G.; Rack, K.; Buckle, V.J.; Wainscoat, J.S. Clonality of cell populations in refractory anaemia using combined approach of gene loss and X-linked restriction fragment length polymorphism-methylation analyses. Br. J. Haematol., 1991, 79(4), 550-555.
[http://dx.doi.org/10.1111/j.1365-2141.1991.tb08080.x] [PMID: 1685326]
[24]
Adamson, J.W.; Fialkow, P.J.; Murphy, S.; Prchal, J.F.; Steinmann, L. Polycythemia vera: stem-cell and probable clonal origin of the disease. N. Engl. J. Med., 1976, 295(17), 913-916.
[http://dx.doi.org/10.1056/NEJM197610212951702] [PMID: 967201]
[25]
Bartram, C.R.; Ludwig, W.D.; Hiddemann, W.; Lyons, J.; Buschle, M.; Ritter, J.; Harbott, J.; Fröhlich, A.; Janssen, J.W. Acute myeloid leukemia: analysis of ras gene mutations and clonality defined by polymorphic X-linked loci. Leukemia, 1989, 3(4), 247-256.
[PMID: 2564452]
[26]
Fialkow, P.J.; Gartler, S.M.; Yoshida, A. Clonal origin of chronic myelocytic leukemia in man. Proc. Natl. Acad. Sci. USA, 1967, 58(4), 1468-1471.
[http://dx.doi.org/10.1073/pnas.58.4.1468] [PMID: 5237880]
[27]
Janssen, J.W.; Buschle, M.; Layton, M.; Lyons, J.; Bartram, C.R. RAS gene mutations and clonal analysis using RFLPs of X-chromosome genes in myelodysplastic syndromes. Haematol. Blood Transfus., 1989, 32, 386-389.
[http://dx.doi.org/10.1007/978-3-642-74621-5_65] [PMID: 2576237]
[28]
Tefferi, A.; Thibodeau, S.N.; Solberg, L.A. Jr. Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphisms. Blood, 1990, 75(9), 1770-1773.
[PMID: 1970487]
[29]
van Kamp, H.; Fibbe, W.E.; Jansen, R.P.; van der Keur, M.; de Graaff, E.; Willemze, R.; Landegent, J.E. Clonal involvement of granulocytes and monocytes, but not of T and B lymphocytes and natural killer cells in patients with myelodysplasia: analysis by X-linked restriction fragment length polymorphisms and polymerase chain reaction of the phosphoglycerate kinase gene. Blood, 1992, 80(7), 1774-1780.
[PMID: 1356510]
[30]
Wiggans, R.G.; Jacobson, R.J.; Fialkow, P.J.; Woolley, P.V., III; Macdonald, J.S.; Schein, P.S. Probable clonal origin of acute myeloblastic leukemia following radiation and chemotherapy of colon cancer. Blood, 1978, 52(4), 659-663.
[PMID: 278630]
[31]
Champion, K.M.; Gilbert, J.G.; Asimakopoulos, F.A.; Hinshelwood, S.; Green, A.R. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br. J. Haematol., 1997, 97(4), 920-926.
[http://dx.doi.org/10.1046/j.1365-2141.1997.1933010.x] [PMID: 9217198]
[32]
da Silva-Coelho, P.; Kroeze, L.I.; Yoshida, K.; Koorenhof-Scheele, T.N.; Knops, R.; van de Locht, L.T.; de Graaf, A.O.; Massop, M.; Sandmann, S.; Dugas, M.; Stevens-Kroef, M.J.; Cermak, J.; Shiraishi, Y.; Chiba, K.; Tanaka, H.; Miyano, S.; de Witte, T.; Blijlevens, N.M.A.; Muus, P.; Huls, G.; van der Reijden, B.A.; Ogawa, S.; Jansen, J.H. Clonal evolution in myelodysplastic syndromes. Nat. Commun., 2017, 8, 15099.
[http://dx.doi.org/10.1038/ncomms15099] [PMID: 28429724]
[33]
Bejar, R.; Stevenson, K.; Abdel-Wahab, O.; Galili, N.; Nilsson, B.; Garcia-Manero, G.; Kantarjian, H.; Raza, A.; Levine, R.L.; Neuberg, D.; Ebert, B.L. Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med., 2011, 364(26), 2496-2506.
[http://dx.doi.org/10.1056/NEJMoa1013343] [PMID: 21714648]
[34]
Papaemmanuil, E.; Gerstung, M.; Malcovati, L.; Tauro, S.; Gundem, G.; Van Loo, P.; Yoon, C.J.; Ellis, P.; Wedge, D.C.; Pellagatti, A.; Shlien, A.; Groves, M.J.; Forbes, S.A.; Raine, K.; Hinton, J.; Mudie, L.J.; McLaren, S.; Hardy, C.; Latimer, C.; Della Porta, M.G.; O’Meara, S.; Ambaglio, I.; Galli, A.; Butler, A.P.; Walldin, G.; Teague, J.W.; Quek, L.; Sternberg, A.; Gambacorti-Passerini, C.; Cross, N.C.; Green, A.R.; Boultwood, J.; Vyas, P.; Hellstrom-Lindberg, E.; Bowen, D.; Cazzola, M.; Stratton, M.R.; Campbell, P.J. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood, 2013, 122(22), 3616-3627.
[http://dx.doi.org/10.1182/blood-2013-08-518886] [PMID: 24030381]
[35]
Cazzola, M.; Della Porta, M.G.; Malcovati, L. The genetic basis of myelodysplasia and its clinical relevance. Blood, 2013, 122(25), 4021-4034.
[http://dx.doi.org/10.1182/blood-2013-09-381665] [PMID: 24136165]
[36]
Kulasekararaj, A.G.; Mohamedali, A.M.; Mufti, G.J. Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes. Br. J. Haematol., 2013, 162(5), 587-605.
[http://dx.doi.org/10.1111/bjh.12435] [PMID: 23869491]
[37]
Haferlach, T.; Nagata, Y.; Grossmann, V.; Okuno, Y.; Bacher, U.; Nagae, G.; Schnittger, S.; Sanada, M.; Kon, A.; Alpermann, T.; Yoshida, K.; Roller, A.; Nadarajah, N.; Shiraishi, Y.; Shiozawa, Y.; Chiba, K.; Tanaka, H.; Koeffler, H.P.; Klein, H.U.; Dugas, M.; Aburatani, H.; Kohlmann, A.; Miyano, S.; Haferlach, C.; Kern, W.; Ogawa, S. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia, 2014, 28(2), 241-247.
[http://dx.doi.org/10.1038/leu.2013.336] [PMID: 24220272]
[38]
Döhner, H.; Estey, E.; Grimwade, D.; Amadori, S.; Appelbaum, F.R.; Büchner, T.; Dombret, H.; Ebert, B.L.; Fenaux, P.; Larson, R.A.; Levine, R.L.; Lo-Coco, F.; Naoe, T.; Niederwieser, D.; Ossenkoppele, G.J.; Sanz, M.; Sierra, J.; Tallman, M.S.; Tien, H.F.; Wei, A.H.; Löwenberg, B.; Bloomfield, C.D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 2017, 129(4), 424-447.
[http://dx.doi.org/10.1182/blood-2016-08-733196] [PMID: 27895058]
[39]
Itzykson, R.; Duployez, N.; Fasan, A.; Decool, G.; Marceau-Renaut, A.; Meggendorfer, M.; Jourdan, E.; Petit, A.; Lapillonne, H.; Micol, J.B.; Cornillet-Lefebvre, P.; Ifrah, N.; Leverger, G.; Dombret, H.; Boissel, N.; Haferlach, T.; Preudhomme, C. Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia. Blood, 2018, 132(2), 187-196.
[http://dx.doi.org/10.1182/blood-2018-03-837781] [PMID: 29692343]
[40]
Busque, L.; Patel, J.P.; Figueroa, M.E.; Vasanthakumar, A.; Provost, S.; Hamilou, Z.; Mollica, L.; Li, J.; Viale, A.; Heguy, A.; Hassimi, M.; Socci, N.; Bhatt, P.K.; Gonen, M.; Mason, C.E.; Melnick, A.; Godley, L.A.; Brennan, C.W.; Abdel-Wahab, O.; Levine, R.L. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet., 2012, 44(11), 1179-1181.
[http://dx.doi.org/10.1038/ng.2413] [PMID: 23001125]
[41]
Jaiswal, S.; Fontanillas, P.; Flannick, J.; Manning, A.; Grauman, P.V.; Mar, B.G.; Lindsley, R.C.; Mermel, C.H.; Burtt, N.; Chavez, A.; Higgins, J.M.; Moltchanov, V.; Kuo, F.C.; Kluk, M.J.; Henderson, B.; Kinnunen, L.; Koistinen, H.A.; Ladenvall, C.; Getz, G.; Correa, A.; Banahan, B.F.; Gabriel, S.; Kathiresan, S.; Stringham, H.M.; McCarthy, M.I.; Boehnke, M.; Tuomilehto, J.; Haiman, C.; Groop, L.; Atzmon, G.; Wilson, J.G.; Neuberg, D.; Altshuler, D.; Ebert, B.L. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med., 2014, 371(26), 2488-2498.
[http://dx.doi.org/10.1056/NEJMoa1408617] [PMID: 25426837]
[42]
Genovese, G.; Kähler, A.K.; Handsaker, R.E.; Lindberg, J.; Rose, S.A.; Bakhoum, S.F.; Chambert, K.; Mick, E.; Neale, B.M.; Fromer, M.; Purcell, S.M.; Svantesson, O.; Landén, M.; Höglund, M.; Lehmann, S.; Gabriel, S.B.; Moran, J.L.; Lander, E.S.; Sullivan, P.F.; Sklar, P.; Grönberg, H.; Hultman, C.M.; McCarroll, S.A. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med., 2014, 371(26), 2477-2487.
[http://dx.doi.org/10.1056/NEJMoa1409405] [PMID: 25426838]
[43]
Xie, M.; Lu, C.; Wang, J.; McLellan, M.D.; Johnson, K.J.; Wendl, M.C.; McMichael, J.F.; Schmidt, H.K.; Yellapantula, V.; Miller, C.A.; Ozenberger, B.A.; Welch, J.S.; Link, D.C.; Walter, M.J.; Mardis, E.R.; Dipersio, J.F.; Chen, F.; Wilson, R.K.; Ley, T.J.; Ding, L. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med., 2014, 20(12), 1472-1478.
[http://dx.doi.org/10.1038/nm.3733] [PMID: 25326804]
[44]
Smith, C.C.; Wang, Q.; Chin, C.S.; Salerno, S.; Damon, L.E.; Levis, M.J.; Perl, A.E.; Travers, K.J.; Wang, S.; Hunt, J.P.; Zarrinkar, P.P.; Schadt, E.E.; Kasarskis, A.; Kuriyan, J.; Shah, N.P. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature, 2012, 485(7397), 260-263.
[http://dx.doi.org/10.1038/nature11016] [PMID: 22504184]
[45]
Levis, M.; Small, D. FLT3: ITDoes matter in leukemia. Leukemia, 2003, 17(9), 1738-1752.
[http://dx.doi.org/10.1038/sj.leu.2403099] [PMID: 12970773]
[46]
Mrózek, K.; Marcucci, G.; Paschka, P.; Whitman, S.P.; Bloomfield, C.D. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, 2007, 109(2), 431-448.
[http://dx.doi.org/10.1182/blood-2006-06-001149] [PMID: 16960150]
[47]
Carow, C.E.; Levenstein, M.; Kaufmann, S.H.; Chen, J.; Amin, S.; Rockwell, P.; Witte, L.; Borowitz, M.J.; Civin, C.I.; Small, D. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood, 1996, 87(3), 1089-1096.
[PMID: 8562934]
[48]
Lin, P.; Jones, D.; Medeiros, L.J.; Chen, W.; Vega-Vazquez, F.; Luthra, R. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am. J. Clin. Pathol., 2006, 126(4), 530-533.
[http://dx.doi.org/10.1309/JT5BE2L1FGG8P8Y6] [PMID: 16938665]
[49]
Williams, L.; Kelley, H.H.; Meng, X.; Prada, A.; Crisan, D. FLT3 mutations in myeloproliferative neoplasms: the Beaumont experience. Diagn. Mol. Pathol., 2013, 22(3), 156-160.
[http://dx.doi.org/10.1097/PDM.0b013e31828564fe] [PMID: 23846442]
[50]
Wang, M.; He, N.; Tian, T.; Liu, L.; Yu, S.; Ma, D. Mutation analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese patients with myeloproliferative neoplasms. BioMed Res. Int., 2014.2014485645
[http://dx.doi.org/10.1155/2014/485645] [PMID: 24895580]
[51]
Xu, B.; Tian, H.; Zhou, S.Y. [Detection of FLT3 gene and FLT3/ITD gene mutation in chronic myeloid leukemia and its significance Chin. J. Cancer, 2004, 23(10), 1218-1221.
[52]
Annamaneni, S.; Kagita, S.; Gorre, M.; Digumarti, R.R.; Satti, V.; Battini, M.R. Incidence of internal tandem duplications and D835 mutations of FLT3 gene in chronic myeloid leukemia patients from Southern India. Hematology, 2014, 19(3), 129-135.
[http://dx.doi.org/10.1179/1607845413Y.0000000109] [PMID: 23796006]
[53]
Daver, N.; Strati, P.; Jabbour, E.; Kadia, T.; Luthra, R.; Wang, S.; Patel, K.; Ravandi, F.; Cortes, J.; Qin, Dong. X.; Kantarjian, H.; Garcia-Manero, G. FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. Am. J. Hematol., 2013, 88(1), 56-59.
[http://dx.doi.org/10.1002/ajh.23345] [PMID: 23115106]
[54]
Badar, T.; Patel, K.P.; Thompson, P.A.; DiNardo, C.; Takahashi, K.; Cabrero, M.; Borthakur, G.; Cortes, J.; Konopleva, M.; Kadia, T.; Bohannan, Z.; Pierce, S.; Jabbour, E.J.; Ravandi, F.; Daver, N.; Luthra, R.; Kantarjian, H.; Garcia-Manero, G. Detectable FLT3-ITD or RAS mutation at the time of transformation from MDS to AML predicts for very poor outcomes. Leuk. Res., 2015, 39(12), 1367-1374.
[http://dx.doi.org/10.1016/j.leukres.2015.10.005] [PMID: 26547258]
[55]
Kuendgen, A.; Müller-Thomas, C.; Lauseker, M.; Haferlach, T.; Urbaniak, P.; Schroeder, T.; Brings, C.; Wulfert, M.; Meggendorfer, M.; Hildebrandt, B.; Betz, B.; Royer-Pokora, B.; Gattermann, N.; Haas, R.; Germing, U.; Götze, K.S. Efficacy of azacitidine is independent of molecular and clinical characteristics - an analysis of 128 patients with myelodysplastic syndromes or acute myeloid leukemia and a review of the literature. Oncotarget, 2018, 9(45), 27882-27894.
[http://dx.doi.org/10.18632/oncotarget.25328] [PMID: 29963245]
[56]
Stirewalt, D.L.; Radich, J.P. The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer, 2003, 3(9), 650-665.
[http://dx.doi.org/10.1038/nrc1169] [PMID: 12951584]
[57]
Bruserud, Ø.; Hovland, R.; Wergeland, L.; Huang, T.S.; Gjertsen, B.T. Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities. Haematologica, 2003, 88(4), 416-428.
[PMID: 12681969]
[58]
Rosen, D.B.; Minden, M.D.; Kornblau, S.M.; Cohen, A.; Gayko, U.; Putta, S.; Woronicz, J.; Evensen, E.; Fantl, W.J.; Cesano, A. Functional characterization of FLT3 receptor signaling deregulation in acute myeloid leukemia by single cell network profiling (SCNP). PLoS One, 2010, 5(10)e13543
[http://dx.doi.org/10.1371/journal.pone.0013543] [PMID: 21048955]
[59]
Koch, S.; Jacobi, A.; Ryser, M.; Ehninger, G.; Thiede, C. Abnormal localization and accumulation of FLT3-ITD, a mutant receptor tyrosine kinase involved in leukemogenesis. Cells Tissues Organs (Print), 2008, 188(1-2), 225-235.
[http://dx.doi.org/10.1159/000118788] [PMID: 18303245]
[60]
Cauchy, P.; James, S.R.; Zacarias-Cabeza, J.; Ptasinska, A.; Imperato, M.R.; Assi, S.A.; Piper, J.; Canestraro, M.; Hoogenkamp, M.; Raghavan, M.; Loke, J.; Akiki, S.; Clokie, S.J.; Richards, S.J.; Westhead, D.R.; Griffiths, M.J.; Ott, S.; Bonifer, C.; Cockerill, P.N. Chronic FLT3-ITD signaling in acute myeloid leukemia is connected to a specific chromatin signature. Cell Rep., 2015, 12(5), 821-836.
[http://dx.doi.org/10.1016/j.celrep.2015.06.069] [PMID: 26212328]
[61]
Lee, B.H.; Williams, I.R.; Anastasiadou, E.; Boulton, C.L.; Joseph, S.W.; Amaral, S.M.; Curley, D.P.; Duclos, N.; Huntly, B.J.; Fabbro, D.; Griffin, J.D.; Gilliland, D.G. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene, 2005, 24(53), 7882-7892.
[http://dx.doi.org/10.1038/sj.onc.1208933] [PMID: 16116483]
[62]
Thiede, C.; Steudel, C.; Mohr, B.; Schaich, M.; Schäkel, U.; Platzbecker, U.; Wermke, M.; Bornhäuser, M.; Ritter, M.; Neubauer, A.; Ehninger, G.; Illmer, T. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 2002, 99(12), 4326-4335.
[http://dx.doi.org/10.1182/blood.V99.12.4326] [PMID: 12036858]
[63]
Konig, H.; Levis, M. Targeting FLT3 to treat leukemia. Expert Opin. Ther. Targets, 2015, 19(1), 37-54.
[http://dx.doi.org/10.1517/14728222.2014.960843] [PMID: 25231999]
[64]
Stone, R.M.; Mandrekar, S.J.; Sanford, B.L.; Laumann, K.; Geyer, S.; Bloomfield, C.D.; Thiede, C.; Prior, T.W.; Döhner, K.; Marcucci, G.; Lo-Coco, F.; Klisovic, R.B.; Wei, A.; Sierra, J.; Sanz, M.A.; Brandwein, J.M.; de Witte, T.; Niederwieser, D.; Appelbaum, F.R.; Medeiros, B.C.; Tallman, M.S.; Krauter, J.; Schlenk, R.F.; Ganser, A.; Serve, H.; Ehninger, G.; Amadori, S.; Larson, R.A.; Döhner, H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med., 2017, 377(5), 454-464.
[http://dx.doi.org/10.1056/NEJMoa1614359] [PMID: 28644114]
[65]
Usuki, K.; Sakura, T.; Kobayashi, Y.; Miyamoto, T.; Iida, H.; Morita, S.; Bahceci, E.; Kaneko, M.; Kusano, M.; Yamada, S.; Takeshita, S.; Miyawaki, S.; Naoe, T. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study. Cancer Sci., 2018, 109(10), 3235-3244.
[http://dx.doi.org/10.1111/cas.13749] [PMID: 30039554]
[66]
Brackertz, B.; Conrad, H.; Daniel, J.; Kast, B.; Krönig, H.; Busch, D.H.; Adamski, J.; Peschel, C.; Bernhard, H. FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes. Blood Cancer J., 2011, 1(3)e11
[http://dx.doi.org/10.1038/bcj.2011.12] [PMID: 22829124]
[67]
Di Stasi, A.; Jimenez, A.M.; Minagawa, K.; Al-Obaidi, M.; Rezvani, K. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front. Immunol., 2015, 6, 36.
[http://dx.doi.org/10.3389/fimmu.2015.00036] [PMID: 25699052]
[68]
Rosenblatt, J.; Stone, R.M.; Uhl, L.; Neuberg, D.; Joyce, R.; Levine, J.D.; Arnason, J.; McMasters, M.; Luptakova, K.; Jain, S.; Zwicker, J.I.; Hamdan, A.; Boussiotis, V.; Steensma, D.P.; DeAngelo, D.J.; Galinsky, I.; Dutt, P.S.; Logan, E.; Bryant, M.P.; Stroopinsky, D.; Werner, L.; Palmer, K.; Coll, M.; Washington, A.; Cole, L.; Kufe, D.; Avigan, D. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci. Transl. Med., 2016, 8(368)368ra171
[http://dx.doi.org/10.1126/scitranslmed.aag1298] [PMID: 27928025]
[69]
Scholl, S.; Salzmann, S.; Kaufmann, A.M.; Höffken, K. Flt3-ITD mutations can generate leukaemia specific neoepitopes: potential role for immunotherapeutic approaches. Leuk. Lymphoma, 2006, 47(2), 307-312.
[http://dx.doi.org/10.1080/10428190500301306] [PMID: 16321862]
[70]
Graf, C.; Heidel, F.; Tenzer, S.; Radsak, M.P.; Solem, F.K.; Britten, C.M.; Huber, C.; Fischer, T.; Wölfel, T. A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells. Blood, 2007, 109(7), 2985-2988.
[PMID: 17119119]
[71]
Schnittger, S.; Schoch, C.; Dugas, M.; Kern, W.; Staib, P.; Wuchter, C.; Löffler, H.; Sauerland, C.M.; Serve, H.; Büchner, T.; Haferlach, T.; Hiddemann, W. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood, 2002, 100(1), 59-66.
[http://dx.doi.org/10.1182/blood.V100.1.59] [PMID: 12070009]
[72]
Stirewalt, D.L.; Kopecky, K.J.; Meshinchi, S.; Engel, J.H.; Pogosova-Agadjanyan, E.L.; Linsley, J.; Slovak, M.L.; Willman, C.L.; Radich, J.P. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood, 2006, 107(9), 3724-3726.
[http://dx.doi.org/10.1182/blood-2005-08-3453] [PMID: 16368883]
[73]
Levis, M.; Murphy, K.M.; Pham, R.; Kim, K.T.; Stine, A.; Li, L.; McNiece, I.; Smith, B.D.; Small, D. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood, 2005, 106(2), 673-680.
[http://dx.doi.org/10.1182/blood-2004-05-1902] [PMID: 15797998]
[74]
Hofmann, M.; Große-Hovest, L.; Nübling, T.; Pyż, E.; Bamberg, M.L.; Aulwurm, S.; Bühring, H.J.; Schwartz, K.; Haen, S.P.; Schilbach, K.; Rammensee, H.G.; Salih, H.R.; Jung, G. Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia. Leukemia, 2012, 26(6), 1228-1237.
[http://dx.doi.org/10.1038/leu.2011.372] [PMID: 22289926]
[75]
Durben, M.; Schmiedel, D.; Hofmann, M.; Vogt, F.; Nübling, T.; Pyz, E.; Bühring, H.J.; Rammensee, H.G.; Salih, H.R.; Große-Hovest, L.; Jung, G. Characterization of a bispecific FLT3 X CD3 antibody in an improved, recombinant format for the treatment of leukemia. Mol. Ther., 2015, 23(4), 648-655.
[http://dx.doi.org/10.1038/mt.2015.2] [PMID: 25578618]
[76]
Reiter, K.; Polzer, H.; Krupka, C.; Maiser, A.; Vick, B.; Rothenberg-Thurley, M.; Metzeler, K.H.; Dörfel, D.; Salih, H.R.; Jung, G.; Nößner, E.; Jeremias, I.; Hiddemann, W.; Leonhardt, H.; Spiekermann, K.; Subklewe, M.; Greif, P.A. Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia. Leukemia, 2018, 32(2), 313-322.
[http://dx.doi.org/10.1038/leu.2017.257] [PMID: 28895560]
[77]
Chen, L.; Mao, H.; Zhang, J.; Chu, J.; Devine, S.; Caligiuri, M.A.; Yu, J. Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia, 2017, 31(8), 1830-1834.
[http://dx.doi.org/10.1038/leu.2017.147] [PMID: 28496177]
[78]
Jetani, H.; Garcia-Cadenas, I.; Nerreter, T.; Thomas, S.; Rydzek, J.; Meijide, J.B.; Bonig, H.; Herr, W.; Sierra, J.; Einsele, H.; Hudecek, M. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia, 2018, 32(5), 1168-1179.
[http://dx.doi.org/10.1038/s41375-018-0009-0] [PMID: 29472720]
[79]
Wang, Y.; Xu, Y.; Li, S.; Liu, J.; Xing, Y.; Xing, H.; Tian, Z.; Tang, K.; Rao, Q.; Wang, M.; Wang, J. Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. J. Hematol. Oncol., 2018, 11(1), 60.
[http://dx.doi.org/10.1186/s13045-018-0603-7] [PMID: 29716633]
[80]
Vainchenker, W.; Constantinescu, S.N. JAK/STAT signaling in hematological malignancies. Oncogene, 2013, 32(21), 2601-2613.
[http://dx.doi.org/10.1038/onc.2012.347] [PMID: 22869151]
[81]
Ihle, J.N. The Janus kinase family and signaling through members of the cytokine receptor superfamily. Proc. Soc. Exp. Biol. Med., 1994, 206(3), 268-272.
[http://dx.doi.org/10.3181/00379727-206-43757] [PMID: 7517047]
[82]
Ihle, J.N. Signaling by the cytokine receptor superfamily in normal and transformed hematopoietic cells. Adv. Cancer Res., 1996, 68, 23-65.
[http://dx.doi.org/10.1016/S0065-230X(08)60351-6] [PMID: 8712070]
[83]
Parganas, E.; Wang, D.; Stravopodis, D.; Topham, D.J.; Marine, J.C.; Teglund, S.; Vanin, E.F.; Bodner, S.; Colamonici, O.R.; van Deursen, J.M.; Grosveld, G.; Ihle, J.N. Jak2 is essential for signaling through a variety of cytokine receptors. Cell, 1998, 93(3), 385-395.
[http://dx.doi.org/10.1016/S0092-8674(00)81167-8] [PMID: 9590173]
[84]
Darnell, J.E. Jr STATs and gene regulation. Science, 1997, 277(5332), 1630-1635.
[http://dx.doi.org/10.1126/science.277.5332.1630] [PMID: 9287210]
[85]
Remy, I.; Wilson, I.A.; Michnick, S.W. Erythropoietin receptor activation by a ligand-induced conformation change. Science, 1999, 283(5404), 990-993.
[http://dx.doi.org/10.1126/science.283.5404.990] [PMID: 9974393]
[86]
Casanova, J.L.; Holland, S.M.; Notarangelo, L.D. Inborn errors of human JAKs and STATs. Immunity, 2012, 36(4), 515-528.
[http://dx.doi.org/10.1016/j.immuni.2012.03.016] [PMID: 22520845]
[87]
Darnell, J.E., Jr; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164), 1415-1421.
[http://dx.doi.org/10.1126/science.8197455] [PMID: 8197455]
[88]
Hoey, T.; Schindler, U. STAT structure and function in signaling. Curr. Opin. Genet. Dev., 1998, 8(5), 582-587.
[http://dx.doi.org/10.1016/S0959-437X(98)80015-4] [PMID: 9794817]
[89]
Parisien, J.P.; Lau, J.F.; Rodriguez, J.J.; Ulane, C.M.; Horvath, C.M. Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction. J. Virol., 2002, 76(9), 4190-4198.
[http://dx.doi.org/10.1128/JVI.76.9.4190-4198.2002] [PMID: 11932384]
[90]
Patnaik, M.M.; Tefferi, A. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management. Am. J. Hematol., 2017, 92(3), 297-310.
[http://dx.doi.org/10.1002/ajh.24637] [PMID: 28188970]
[91]
Pellagatti, A.; Boultwood, J. The molecular pathogenesis of the myelodysplastic syndromes. Eur. J. Haematol., 2015, 95(1), 3-15.
[http://dx.doi.org/10.1111/ejh.12515] [PMID: 25645650]
[92]
Hoefsloot, L.H.; van Amelsvoort, M.P.; Broeders, L.C.; van der Plas, D.C.; van Lom, K.; Hoogerbrugge, H.; Touw, I.P.; Löwenberg, B. Erythropoietin-induced activation of STAT5 is impaired in the myelodysplastic syndrome. Blood, 1997, 89(5), 1690-1700.
[PMID: 9057652]
[93]
Vannucchi, A.M.; Kiladjian, J.J.; Griesshammer, M.; Masszi, T.; Durrant, S.; Passamonti, F.; Harrison, C.N.; Pane, F.; Zachee, P.; Mesa, R.; He, S.; Jones, M.M.; Garrett, W.; Li, J.; Pirron, U.; Habr, D.; Verstovsek, S. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N. Engl. J. Med., 2015, 372(5), 426-435.
[http://dx.doi.org/10.1056/NEJMoa1409002] [PMID: 25629741]
[94]
Mascarenhas, J.O.; Talpaz, M.; Gupta, V.; Foltz, L.M.; Savona, M.R.; Paquette, R.; Turner, A.R.; Coughlin, P.; Winton, E.; Burn, T.C.; O’Neill, P.; Clark, J.; Hunter, D.; Assad, A.; Hoffman, R.; Verstovsek, S. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica, 2017, 102(2), 327-335.
[http://dx.doi.org/10.3324/haematol.2016.151126] [PMID: 27789678]
[95]
Mesa, R.A.; Vannucchi, A.M.; Mead, A.; Egyed, M.; Szoke, A.; Suvorov, A.; Jakucs, J.; Perkins, A.; Prasad, R.; Mayer, J.; Demeter, J.; Ganly, P.; Singer, J.W.; Zhou, H.; Dean, J.P.; Te Boekhorst, P.A.; Nangalia, J.; Kiladjian, J.J.; Harrison, C.N. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol., 2017, 4(5), e225-e236.
[http://dx.doi.org/10.1016/S2352-3026(17)30027-3] [PMID: 28336242]
[96]
Pardanani, A.; Tefferi, A.; Jamieson, C.; Gabrail, N.Y.; Lebedinsky, C.; Gao, G.; Liu, F.; Xu, C.; Cao, H.; Talpaz, M. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J., 2015, 5e335
[http://dx.doi.org/10.1038/bcj.2015.63] [PMID: 26252788]
[97]
Verstovsek, S.; Mesa, R.A.; Salama, M.E.; Li, L.; Pitou, C.; Nunes, F.P.; Price, G.L.; Giles, J.L.; D’Souza, D.N.; Walgren, R.A.; Prchal, J.T. A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Leuk. Res., 2017, 61, 89-95.
[http://dx.doi.org/10.1016/j.leukres.2017.08.010] [PMID: 28934680]
[98]
Mohapatra, B.; Ahmad, G.; Nadeau, S.; Zutshi, N.; An, W.; Scheffe, S.; Dong, L.; Feng, D.; Goetz, B.; Arya, P.; Bailey, T.A.; Palermo, N.; Borgstahl, G.E.; Natarajan, A.; Raja, S.M.; Naramura, M.; Band, V.; Band, H. Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim. Biophys. Acta, 2013, 1833(1), 122-139.
[http://dx.doi.org/10.1016/j.bbamcr.2012.10.010] [PMID: 23085373]
[99]
Thien, C.B.; Langdon, W.Y. c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. Biochem. J., 2005, 391(Pt 2), 153-166.
[http://dx.doi.org/10.1042/BJ20050892] [PMID: 16212556]
[100]
Rathinam, C.; Thien, C.B.; Langdon, W.Y.; Gu, H. Flavell, R.A. The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells. Genes Dev., 2008, 22(8), 992-997.
[http://dx.doi.org/10.1101/gad.1651408] [PMID: 18413713]
[101]
Sanada, M.; Suzuki, T.; Shih, L.Y.; Otsu, M.; Kato, M.; Yamazaki, S.; Tamura, A.; Honda, H.; Sakata-Yanagimoto, M.; Kumano, K.; Oda, H.; Yamagata, T.; Takita, J.; Gotoh, N.; Nakazaki, K.; Kawamata, N.; Onodera, M.; Nobuyoshi, M.; Hayashi, Y.; Harada, H.; Kurokawa, M.; Chiba, S.; Mori, H.; Ozawa, K.; Omine, M.; Hirai, H.; Nakauchi, H.; Koeffler, H.P.; Ogawa, S. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature, 2009, 460(7257), 904-908.
[http://dx.doi.org/10.1038/nature08240] [PMID: 19620960]
[102]
Bachmaier, K.; Krawczyk, C.; Kozieradzki, I.; Kong, Y.Y.; Sasaki, T.; Oliveira-dos-Santos, A.; Mariathasan, S.; Bouchard, D.; Wakeham, A.; Itie, A.; Le, J.; Ohashi, P.S.; Sarosi, I.; Nishina, H.; Lipkowitz, S.; Penninger, J.M. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature, 2000, 403(6766), 211-216.
[http://dx.doi.org/10.1038/35003228] [PMID: 10646608]
[103]
Chiang, Y.J.; Kole, H.K.; Brown, K.; Naramura, M.; Fukuhara, S.; Hu, R.J.; Jang, I.K.; Gutkind, J.S.; Shevach, E.; Gu, H. Cbl-b regulates the CD28 dependence of T-cell activation. Nature, 2000, 403(6766), 216-220.
[http://dx.doi.org/10.1038/35003235] [PMID: 10646609]
[104]
Murphy, M.A.; Schnall, R.G.; Venter, D.J.; Barnett, L.; Bertoncello, I.; Thien, C.B.; Langdon, W.Y.; Bowtell, D.D. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol. Cell. Biol., 1998, 18(8), 4872-4882.
[http://dx.doi.org/10.1128/MCB.18.8.4872] [PMID: 9671496]
[105]
Naramura, M.; Kole, H.K.; Hu, R.J.; Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl. Acad. Sci. USA, 1998, 95(26), 15547-15552.
[http://dx.doi.org/10.1073/pnas.95.26.15547] [PMID: 9861006]
[106]
Reindl, C.; Quentmeier, H.; Petropoulos, K.; Greif, P.A.; Benthaus, T.; Argiropoulos, B.; Mellert, G.; Vempati, S.; Duyster, J.; Buske, C.; Bohlander, S.K.; Humphries, K.R.; Hiddemann, W.; Spiekermann, K. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin. Cancer Res., 2009, 15(7), 2238-2247.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1325] [PMID: 19276253]
[107]
Ikushima, H.; Miyazono, K. Cellular context-dependent “colors” of transforming growth factor-beta signaling. Cancer Sci., 2010, 101(2), 306-312.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01441.x] [PMID: 20067465]
[108]
Zuo, W.; Huang, F.; Chiang, Y.J.; Li, M.; Du, J.; Ding, Y.; Zhang, T.; Lee, H.W.; Jeong, L.S.; Chen, Y.; Deng, H.; Feng, X.H.; Luo, S.; Gao, C.; Chen, Y.G. c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor. Mol. Cell, 2013, 49(3), 499-510.
[http://dx.doi.org/10.1016/j.molcel.2012.12.002] [PMID: 23290524]
[109]
Bhagat, T.D.; Zhou, L.; Sokol, L.; Kessel, R.; Caceres, G.; Gundabolu, K.; Tamari, R.; Gordon, S.; Mantzaris, I.; Jodlowski, T.; Yu, Y.; Jing, X.; Polineni, R.; Bhatia, K.; Pellagatti, A.; Boultwood, J.; Kambhampati, S.; Steidl, U.; Stein, C.; Ju, W.; Liu, G.; Kenny, P.; List, A.; Bitzer, M.; Verma, A. miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood, 2013, 121(15), 2875-2881.
[http://dx.doi.org/10.1182/blood-2011-12-397067] [PMID: 23390194]
[110]
Zhou, L.; Nguyen, A.N.; Sohal, D.; Ying , Ma. J.; Pahanish, P.; Gundabolu, K.; Hayman, J.; Chubak, A.; Mo, Y.; Bhagat, T.D.; Das, B.; Kapoun, A.M.; Navas, T.A.; Parmar, S.; Kambhampati, S.; Pellagatti, A.; Braunchweig, I.; Zhang, Y.; Wickrema, A.; Medicherla, S.; Boultwood, J.; Platanias, L.C.; Higgins, L.S.; List, A.F.; Bitzer, M.; Verma, A. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood, 2008, 112(8), 3434-3443.
[http://dx.doi.org/10.1182/blood-2008-02-139824] [PMID: 18474728]
[111]
Zhou, L.; McMahon, C.; Bhagat, T.; Alencar, C.; Yu, Y.; Fazzari, M.; Sohal, D.; Heuck, C.; Gundabolu, K.; Ng, C.; Mo, Y.; Shen, W.; Wickrema, A.; Kong, G.; Friedman, E.; Sokol, L.; Mantzaris, I.; Pellagatti, A.; Boultwood, J.; Platanias, L.C.; Steidl, U.; Yan, L.; Yingling, J.M.; Lahn, M.M.; List, A.; Bitzer, M.; Verma, A. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res., 2011, 71(3), 955-963.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2933] [PMID: 21189329]
[112]
Attie, K.M.; Allison, M.J.; McClure, T.; Boyd, I.E.; Wilson, D.M.; Pearsall, A.E.; Sherman, M.L. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am. J. Hematol., 2014, 89(7), 766-770.
[http://dx.doi.org/10.1002/ajh.23732] [PMID: 24715706]
[113]
Suragani, R.N.; Cadena, S.M.; Cawley, S.M.; Sako, D.; Mitchell, D.; Li, R.; Davies, M.V.; Alexander, M.J.; Devine, M.; Loveday, K.S.; Underwood, K.W.; Grinberg, A.V.; Quisel, J.D.; Chopra, R.; Pearsall, R.S.; Seehra, J.; Kumar, R. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat. Med., 2014, 20(4), 408-414.
[http://dx.doi.org/10.1038/nm.3512] [PMID: 24658078]
[114]
Goodsell, D.S. The molecular perspective: the ras oncogene. Oncologist, 1999, 4(3), 263-264.
[PMID: 10394594]
[115]
Dicker, F.; Haferlach, C.; Sundermann, J.; Wendland, N.; Weiss, T.; Kern, W.; Haferlach, T.; Schnittger, S. Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML. Leukemia, 2010, 24(8), 1528-1532.
[http://dx.doi.org/10.1038/leu.2010.124] [PMID: 20520634]
[116]
Kadia, T.M.; Kantarjian, H.; Kornblau, S.; Borthakur, G.; Faderl, S.; Freireich, E.J.; Luthra, R.; Garcia-Manero, G.; Pierce, S.; Cortes, J.; Ravandi, F. Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS. Cancer, 2012, 118(22), 5550-5559.
[http://dx.doi.org/10.1002/cncr.27596] [PMID: 22569880]
[117]
Gómez-Seguí, I.; Makishima, H.; Jerez, A.; Yoshida, K.; Przychodzen, B.; Miyano, S.; Shiraishi, Y.; Husseinzadeh, H.D.; Guinta, K.; Clemente, M.; Hosono, N.; McDevitt, M.A.; Moliterno, A.R.; Sekeres, M.A.; Ogawa, S.; Maciejewski, J.P. Novel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies. Leukemia, 2013, 27(9), 1943-1946.
[http://dx.doi.org/10.1038/leu.2013.179] [PMID: 23765226]
[118]
Al-Kali, A.; Quintás-Cardama, A.; Luthra, R.; Bueso-Ramos, C.; Pierce, S.; Kadia, T.; Borthakur, G.; Estrov, Z.; Jabbour, E.; Faderl, S.; Ravandi, F.; Cortes, J.; Tefferi, A.; Kantarjian, H.; Garcia-Manero, G. Prognostic impact of RAS mutations in patients with myelodysplastic syndrome. Am. J. Hematol., 2013, 88(5), 365-369.
[http://dx.doi.org/10.1002/ajh.23410] [PMID: 23512829]
[119]
Xu, Y.; Li, Y.; Xu, Q.; Chen, Y.; Lv, N.; Jing, Y.; Dou, L.; Bo, J.; Hou, G.; Guo, J.; Wang, X.; Wang, L.; Li, Y.; Chen, C.; Yu, L. Implications of mutational spectrum in myelodysplastic syndromes based on targeted next-generation sequencing. Oncotarget, 2017, 8(47), 82475-82490.
[http://dx.doi.org/10.18632/oncotarget.19628] [PMID: 29137279]
[120]
Makishima, H.; Yoshizato, T.; Yoshida, K.; Sekeres, M.A.; Radivoyevitch, T.; Suzuki, H.; Przychodzen, B.; Nagata, Y.; Meggendorfer, M.; Sanada, M.; Okuno, Y.; Hirsch, C.; Kuzmanovic, T.; Sato, Y.; Sato-Otsubo, A.; LaFramboise, T.; Hosono, N.; Shiraishi, Y.; Chiba, K.; Haferlach, C.; Kern, W.; Tanaka, H.; Shiozawa, Y.; Gómez-Seguí, I.; Husseinzadeh, H.D.; Thota, S.; Guinta, K.M.; Dienes, B.; Nakamaki, T.; Miyawaki, S.; Saunthararajah, Y.; Chiba, S.; Miyano, S.; Shih, L.Y.; Haferlach, T.; Ogawa, S.; Maciejewski, J.P. Dynamics of clonal evolution in myelodysplastic syndromes. Nat. Genet., 2017, 49(2), 204-212.
[http://dx.doi.org/10.1038/ng.3742] [PMID: 27992414]
[121]
Heuser, M.; Gabdoulline, R.; Löffeld, P.; Dobbernack, V.; Kreimeyer, H.; Pankratz, M.; Flintrop, M.; Liebich, A.; Klesse, S.; Panagiota, V.; Stadler, M.; Wichmann, M.; Shahswar, R.; Platzbecker, U.; Thiede, C.; Schroeder, T.; Kobbe, G.; Geffers, R.; Schlegelberger, B.; Göhring, G.; Kreipe, H.H.; Germing, U.; Ganser, A.; Kröger, N.; Koenecke, C.; Thol, F. Individual outcome prediction for myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia from MDS after allogeneic hematopoietic cell transplantation. Ann. Hematol., 2017, 96(8), 1361-1372.
[http://dx.doi.org/10.1007/s00277-017-3027-5] [PMID: 28612220]
[122]
Lindsley, R.C.; Saber, W.; Mar, B.G.; Redd, R.; Wang, T.; Haagenson, M.D.; Grauman, P.V.; Hu, Z.H.; Spellman, S.R.; Lee, S.J.; Verneris, M.R.; Hsu, K.; Fleischhauer, K.; Cutler, C.; Antin, J.H.; Neuberg, D.; Ebert, B.L. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N. Engl. J. Med., 2017, 376(6), 536-547.
[http://dx.doi.org/10.1056/NEJMoa1611604] [PMID: 28177873]
[123]
Bowen, D.T.; Frew, M.E.; Hills, R.; Gale, R.E.; Wheatley, K.; Groves, M.J.; Langabeer, S.E.; Kottaridis, P.D.; Moorman, A.V.; Burnett, A.K.; Linch, D.C. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood, 2005, 106(6), 2113-2119.
[http://dx.doi.org/10.1182/blood-2005-03-0867] [PMID: 15951308]
[124]
Garcia-Manero, G.; Fenaux, P.; Al-Kali, A.; Baer, M.R.; Sekeres, M.A.; Roboz, G.J.; Gaidano, G.; Scott, B.L.; Greenberg, P.; Platzbecker, U.; Steensma, D.P.; Kambhampati, S.; Kreuzer, K.A.; Godley, L.A.; Atallah, E.; Collins, R., Jr; Kantarjian, H.; Jabbour, E.; Wilhelm, F.E.; Azarnia, N.; Silverman, L.R. ONTIME study investigators.Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol., 2016, 17(4), 496-508.
[http://dx.doi.org/10.1016/S1470-2045(16)00009-7] [PMID: 26968357]

Rights & Permissions Print Cite
Article Metrics
82
4
© 2024 Bentham Science Publishers | Privacy Policy