Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

Abstract

Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses. The class III subfamily comprises the platelet-derived growth factor receptor, c-Kit, Flt3 and c-Fms, all of which relay cell proliferation signals upon ligand binding. Accordingly, mutations in these proteins that confer ligand-independent activation are found in a subset of cancers. These mutations cluster in the juxtamembrane (JM) and catalytic tyrosine kinase domain (TKD) regions. In the case of acute myeloid leukemia (AML), the juxtamembrane (named ITD for internal tandem duplication) and TKD Flt3 mutants differ in their spectra of clinical outcomes. Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases, the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain. This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation, to account for the disease variation. This will have bearing on therapeutic approaches in a complex disease such as AML, for which no efficacious drug yet exists.

Keywords

acute myeloid leukemia / receptor tyrosine kinase / oncogenic mutation / autoinhibition / intracellular trafficking

References

[1] Chan, P.M., Ilangumaran, S., La Rose, J., Chakrabartty, A., and Rottapel, R. (2003). Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region. Mol Cell Biol 23, 3067–3078 .12697809
[2] Choudhary, C., Brandts, C., Schwable, J., Tickenbrock, L., Sargin, B., Ueker, A., B?hmer, F.D., Berdel, W.E., Müller-Tidow, C., and Serve, H. (2007). Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood 110, 370–374 .17356133
[3] Choudhary, C., Olsen, J.V., Brandts, C., Cox, J., Reddy, P.N., B?hmer, F.D., Gerke, V., Schmidt-Arras, D.E., Berdel, W.E., Müller-Tidow, C., (2009). Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 36, 326–339 .19854140
[4] Choudhary, C., Schw?ble, J., Brandts, C., Tickenbrock, L., Sargin, B., Kindler, T., Fischer, T., Berdel, W.E., Müller-Tidow, C., and Serve, H. (2005). AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 106, 265–273 .15769897
[5] Dosil, M., Wang, S., and Lemischka, I.R. (1993). Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol Cell Biol 13, 6572–6585 .7692230
[6] Gilliland, D.G., and Griffin, J.D. (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood 100, 1532–1542 .12176867
[7] Griffith, J., Black, J., Faerman, C., Swenson, L., Wynn, M., Lu, F., Lippke, J., and Saxena, K. (2004). The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 13, 169–178 .14759363
[8] Grundler, R., Miething, C., Thiede, C., Peschel, C., and Duyster, J. (2005). FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood 105, 4792–4799 .15718420
[9] Hayakawa, F., Towatari, M., Kiyoi, H., Tanimoto, M., Kitamura, T., Saito, H., and Naoe, T. (2000). Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19, 624–631 .10698507
[10] Heiss, E., Masson, K., Sundberg, C., Pedersen, M., Sun, J., Bengtsson, S., and R?nnstrand, L. (2006). Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood 108, 1542–1550 .16684964
[11] Huntly, B.J., and Gilliland, D.G. (2005). Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5, 311–321 .15803157
[12] Kindler, T., Lipka, D.B., and Fischer, T. (2010). FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 116, 5089–5102 .20705759
[13] Kiyoi, H., Naoe, T., Nakano, Y., Yokota, S., Minami, S., Miyawaki, S., Asou, N., Kuriyama, K., Jinnai, I., Shimazaki, C., (1999). Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93, 3074–3080 .10216104
[14] Kiyoi, H., Ohno, R., Ueda, R., Saito, H., and Naoe, T. (2002). Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 21, 2555–2563 .11971190
[15] Koch, S., Jacobi, A., Ryser, M., Ehninger, G., and Thiede, C. (2008). Abnormal localization and accumulation of FLT3-ITD, a mutant receptor tyrosine kinase involved in leukemogenesis. Cells Tissues Organs 188, 225–235 .18303245
[16] Kottaridis, P.D., Gale, R.E., Frew, M.E., Harrison, G., Langabeer, S.E., Belton, A.A., Walker, H., Wheatley, K., Bowen, D.T., Burnett, A.K., (2001). The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98, 1752–1759 .11535508
[17] Levis, M., and Small, D. (2003). FLT3: ITDoes matter in leukemia. Leukemia 17, 1738–1752 .12970773
[18] Lu, Y., Kitaura, J., Oki, T., Komeno, Y., Ozaki, K., Kiyono, M., Kumagai, H., Nakajima, H., Nosaka, T., Aburatani, H., (2007). Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD. Leukemia 21, 2246–2257 .17690703
[19] Mackarehtschian, K., Hardin, J.D., Moore, K.A., Boast, S., Goff, S.P., and Lemischka, I.R. (1995). Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147–161 .7621074
[20] Masson, K., Heiss, E., Band, H., and R?nnstrand, L. (2006). Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. Biochem J 399, 59–67 .16780420
[21] Masson, K., and R?nnstrand, L. (2009). Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3. Cell Signal 21, 1717–1726 .19540337
[22] Matthews, W., Jordan, C.T., Wiegand, G.W., Pardoll, D., and Lemischka, I.R. (1991). A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65, 1143–1152 .1648448
[23] Mayer, B.J., Hirai, H., and Sakai, R. (1995). Evidence that SH2 domains promote processive phosphorylation by protein-tyrosine kinases. Curr Biol 5, 296–305 .7780740
[24] Meshinchi, S., Alonzo, T.A., Stirewalt, D.L., Zwaan, M., Zimmerman, M., Reinhardt, D., Kaspers, G.J., Heerema, N.A., Gerbing, R., Lange, B.J., (2006). Clinical implications of FLT3 mutations in pediatric AML. Blood 108, 3654–3661 .16912228
[25] Meshinchi, S., and Appelbaum, F.R. (2009). Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 15, 4263–4269 .19549778
[26] Mol, C.D., Dougan, D.R., Schneider, T.R., Skene, R.J., Kraus, M.L., Scheibe, D.N., Snell, G.P., Zou, H., Sang, B.C., and Wilson, K.P. (2004). Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279, 31655–31663 .15123710
[27] Mol, C.D., Lim, K.B., Sridhar, V., Zou, H., Chien, E.Y., Sang, B.C., Nowakowski, J., Kassel, D.B., Cronin, C.N., and McRee, D.E. (2003). Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem 278, 31461–31464 .12824176
[28] Murata, K., Kumagai, H., Kawashima, T., Tamitsu, K., Irie, M., Nakajima, H., Suzu, S., Shibuya, M., Kamihira, S., Nosaka, T., (2003). Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem 278, 32892–32898 .12815052
[29] Nakao, M., Yokota, S., Iwai, T., Kaneko, H., Horiike, S., Kashima, K., Sonoda, Y., Fujimoto, T., and Misawa, S. (1996). Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10, 1911–1918 .8946930
[30] Ong, S.E., Blagoev, B., Kratchmarova, I., Kristensen, D.B., Steen, H., Pandey, A., and Mann, M. (2002). Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 1, 376–386 .12118079
[31] Pratz, K.W., Cortes, J., Roboz, G.J., Rao, N., Arowojolu, O., Stine, A., Shiotsu, Y., Shudo, A., Akinaga, S., Small, D., (2009). A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 113, 3938–3946 .19029442
[32] Razumovskaya, E., Masson, K., Khan, R., Bengtsson, S., and R?nnstrand, L. (2009). Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation. Exp Hematol 37, 979–989 .19477218
[33] Rocnik, J.L., Okabe, R., Yu, J.C., Lee, B.H., Giese, N., Schenkein, D.P., and Gilliland, D.G. (2006). Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 108, 1339–1345 .16627759
[34] Sargin, B., Choudhary, C., Crosetto, N., Schmidt, M.H., Grundler, R., Rensinghoff, M., Thiessen, C., Tickenbrock, L., Schw?ble, J., Brandts, C., (2007). Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110, 1004–1012 .17446348
[35] Schmidt-Arras, D., B?hmer, S.A., Koch, S., Müller, J.P., Blei, L., Cornils, H., Bauer, R., Korasikha, S., Thiede, C., and B?hmer, F.D. (2009). Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality. Blood 113, 3568–3576 .19204327
[36] Small, D., Levenstein, M., Kim, E., Carow, C., Amin, S., Rockwell, P., Witte, L., Burrow, C., Ratajczak, M.Z., Gewirtz, A.M., (1994). STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A 91, 459–463 .7507245
[37] Stirewalt, D.L., Kopecky, K.J., Meshinchi, S., Engel, J.H., Pogosova-Agadjanyan, E.L., Linsley, J., Slovak, M.L., Willman, C.L., and Radich, J.P. (2006). Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 107, 3724–3726 .16368883
[38] Stirewalt, D.L., and Radich, J.P. (2003). The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3, 650–665 .12951584
[39] Tickenbrock, L., Schw?ble, J., Wiedehage, M., Steffen, B., Sargin, B., Choudhary, C., Brandts, C., Berdel, W.E., Müller-Tidow, C., and Serve, H. (2005). Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 105, 3699–3706 .15650056
[40] Till, J.H., Chan, P.M., and Miller, W.T. (1999). Engineering the substrate specificity of the Abl tyrosine kinase. J Biol Chem 274, 4995–5003 .9988744
[41] Vempati, S., Reindl, C., Wolf, U., Kern, R., Petropoulos, K., Naidu, V.M., Buske, C., Hiddemann, W., Kohl, T.M., and Spiekermann, K. (2008). Transformation by oncogenic mutants and ligand-dependent activation of FLT3 wild-type requires the tyrosine residues 589 and 591. Clin Cancer Res 14, 4437–4445 .18628457
[42] Walter, M., Lucet, I.S., Patel, O., Broughton, S.E., Bamert, R., Williams, N.K., Fantino, E., Wilks, A.F., and Rossjohn, J. (2007). The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain. J Mol Biol 367, 839–847 .17292918
[43] Yamamoto, Y., Kiyoi, H., Nakano, Y., Suzuki, R., Kodera, Y., Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C., (2001). Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97, 2434–2439 .11290608
[44] Zhang, S., and Broxmeyer, H.E. (1999). p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells. Biochem Biophys Res Commun 254, 440–445 .9918857
[45] Zhu, H., Pan, S., Gu, S., Bradbury, E.M., and Chen, X. (2002). Amino acid residue specific stable isotope labeling for quantitative proteomics. Rapid Commun Mass Spectrom 16, 2115–2123 .12415544