Abstract
Mutations of the Fms-like tyrosine kinase 3 (FLT3) can be detected in a significant number of acute myeloid leukemias (AML). Seventy-five cases of acute myeloid leukemia were evaluated for FLT3-internal tandem duplications (ITD) by polymerase chain reaction. Paraffin-embedded formalin-fixed trephine biopsies of these cases were evaluated for expression of phosphorylated signal transducer and activator of transcription 1 (pSTAT1), pSTAT3, and pSTAT5. Specific expression of pSTAT5 was proven in leukemic blasts in situ by double staining with a blast-specific marker. Expression of pSTAT5 in ≥1% of blasts was highly predictive of FLT3-ITD. Neither expression of pSTAT1 nor pSTAT3 were associated with FLT3 mutations. Altogether we conclude that pSTAT5 expression can precisely be assessed by immunohistochemistry in routinely processed bone marrow trephines, STAT5 is highly likely the preferred second messenger of FLT3-mediated signaling in AML, and expression of pSTAT5 is predictive of FLT3-ITD.
Similar content being viewed by others
References
Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P et al (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 USA 91:459–463
Choudhary C, Muller-Tidow C, Berdel WE, Serve H (2005) Signal transduction of oncogenic Flt3. Int J Hematol 82:93–99
Vu HA, Xinh PT, Masuda M, Motoji T, Toyoda A, Sakaki Y et al (2006) FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. Leukemia 20:1414–1421
Tzankov A, Sotlar K, Muhlematter D, Theocharides A, Went P, Jotterand M et al (2008) Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3. J Clin Pathol 61:958–961
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93:3074–3080
Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al (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
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97:2434–2439
Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y et al (2004) Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 103:1901–1908
Reilly JT (2003) FLT3 and its role in the pathogenesis of acute myeloid leukaemia. Leuk Lymphoma 44:1–7
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K et al (1996) Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10:1911–1918
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon
Krebs DL, Hilton DJ (2001) SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19:378–387
Bowman T, Garcia R, Turkson J, Jove R (2000) STATs in oncogenesis. Oncogene 19:2474–2488
Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse JF, Capiod JC, Delobel J et al (1996) STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 87:1692–1697
Xia Z, Baer MR, Block AW, Baumann H, Wetzler M (1998) Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts. Cancer Res 58:3173–3180
Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P et al (2009) Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol 22:476–487
Coffer PJ, Koenderman L, de Groot RP (2000) The role of STATs in myeloid differentiation and leukemia. Oncogene 19:2511–2522
Mui AL, Wakao H, O'Farrell AM, Harada N, Miyajima A (1995) Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J 14:1166–1175
Zhang S, Fukuda S, Lee Y, Hangoc G, Cooper S, Spolski R et al (2000) Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J Exp Med 192:719–728
Castagne C, Muhlematter D, van Melle G, Gachoud V, Jotterand Bellomo M (1997) Effect of conditioned media, nutritive elements, and mitotic synchronization on the accuracy of the cytogenetic analysis in acute nonlymphocytic leukemia patients presenting with inv(16)/t(16;16) or t(15;17). Cancer Genet Cytogenet 94:106–112
Mitelman F (1995) An international system for human cytogenetic nomenclature. Karger, Basel
Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE (2004) Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 104:550–557
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266
Tzankov A, Zlobec I, Went P, Robl H, Hoeller S, Dirnhofer S (2009) Prognostic immunophenotypic biomarker studies in diffuse large B cell lymphoma with special emphasis on rational determination of cut-off scores. Leuk Lymphoma. doi:10.3109/10428190903370338
Pallis M, Seedhouse C, Grundy M, Russell N (2003) Flow cytometric measurement of phosphorylated STAT5 in AML: lack of specific association with FLT3 internal tandem duplications. Leuk Res 27:803–805
Weber-Nordt RM, Egen C, Wehinger J, Ludwig W, Gouilleux-Gruart V, Mertelsmann R et al (1996) Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein–Barr virus (EBV)-related lymphoma cell lines. Blood 88:809–816
Birkenkamp KU, Geugien M, Lemmink HH, Kruijer W, Vellenga E (2001) Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia 15:1923–1931
Spiekermann K, Pau M, Schwab R, Schmieja K, Franzrahe S, Hiddemann W (2002) Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. Exp Hematol 30:262–271
Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP et al (2006) Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 108:1339–1345
Spiekermann K, Dirschinger RJ, Schwab R, Bagrintseva K, Faber F, Buske C et al (2003) The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood 101:1494–1504
Stirewalt DL, Meshinchi S, Radich JP (2003) Molecular targets in acute myelogenous leukemia. Blood 17:15–23
Zhou J, Bi C, Janakakumara JV, Liu SC, Chng WJ, Tay KG et al (2009) Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood 113:4052–4062
Author information
Authors and Affiliations
Corresponding author
Additional information
Ellen C. Obermann and Caroline Arber contributed equally to this work
Rights and permissions
About this article
Cite this article
Obermann, E.C., Arber, C., Jotterand, M. et al. Expression of pSTAT5 predicts FLT3 internal tandem duplications in acute myeloid leukemia. Ann Hematol 89, 663–669 (2010). https://doi.org/10.1007/s00277-009-0890-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-009-0890-8