Demircan ÖZBALCI, Memduh ŞAHİN, İbrahim Celalettin HAZNEDAROĞLU

Peripheral FLT-3 ligand levels as a pathobiological parameter during the clinical course of acute myeloid leukemia

Background/aim: FLT-3 ligand is a growth factor affecting the hematopoietic lineage. The aim of this study was to evaluate the variability of peripheral FLT-3 ligand during the clinical course of acute myeloid leukemia (AML) patients. Materials and methods: Twenty-four patients were enrolled in this study in order to assess alterations in the circulating levels of FLT-3 ligand during the clinical course of AML. Results: We studied the association in the diagnostic period between the FLT-3 ligand and peripheral blood cells together with serum electrolytes. FLT-3 ligand levels (pg/mL) during the aplastic period due to remission induction and consolidation were higher than the levels at initial diagnosis. On the other hand, the diagnostic and remission induction values of leukocytes and FLT-3 ligand showed an inverse association. These results indicate to us that higher white cell counts are associated with lower FLT-3 ligand levels. We also found a reversed association between FLT-3 ligand and serum lactate dehydrogenase level. However, there was no association between FLT-3 ligand and other serum electrolyte levels. We also found higher FLT-3 ligand levels in male patients. Conclusion: Our study demonstrates the inverse proliferative action of FLT-3 ligand on the early myeloid lineage. In addition, this study showed us that FLT-3 receptor inhibition during chemotherapy-induced aplasia causes a compensative ligand overexpression.

PDF

___

1. Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Eng J Med 1999; 341: 1051-1062.
2. Murohashi I, Tohda S, Suzuki T, Nagata K, Yamashita Y, Nara N. Autocrine growth mechanisms of the progenitors of blast cells in acute myeloblastic leukemia. Blood 1989; 74: 35-41.
3. Murohashi I, Endoh K, Feng E, Yoshida K, Hirota H, Yoshida S, Jinnai I, Bessho M, Hirashima K. Roles of stem cell factor in the in vitro growth of blast clonogenic cells from patients with acute myeloblastic leukemia. J Interferon Cytokine Res 1995; 15: 829-835.
4. Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, Hollingsworth LT, Picha KS, McKenna HJ, Splett RR et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75: 1157-1167.
5. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J et al. Ligand for flt3/flk2 receptor regulates growth of hematopoietic stem cells and is encoded by variant RNAs. Nature 1994; 368: 643-648.
6. Lyman SD, James L, Johnson L, Brasel K, de Vries P, Escobar SS, Downey H, Splett RR, Beckmann MP, McKenna HJ. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 1994; 83: 2795-2801.
7. Braun S, Chen K, Blazar BR, Orchard PJ, Sledge G, Robertson MJ, Broxmeyer HE, Cornetta K. Flt-3 ligand antitumor activity in a murine breast cancer model: comparison with granulocyte-macrophage colony-stimulating factor and potential mechanism of action. Hum Gene Ther 1999; 10: 2141-2151.
8. Wang A, Braun SE, Sonpavde G, Cornetta K. Antileukemic activity of Flt3 ligand in murine leukemia. Cancer Res 2000; 60: 1895-1900.
9. Sternberg DW, Licht JD. Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT-3): opportunities and challenges. Curr Opin Hematol 2005; 12: 7-13.
10. Robinson LJ, Xue J, Corey SJ. Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations. Exp Hematol 2005; 33: 469-479.
11. Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S, Small D, Burnett A, Levis M. FLT3 ligand impedes the efficacy of inhibitors in vitro and in vivo. Blood 2011; 117: 3286-3293.
12. Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, Erba H, Stuart RK, Baccarani M, Cripe LD et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011; 117: 3294-3301.
13. Patel PS, Adhvaryu SG, Baxi BR. Tumor markers in leukemia: evaluation of serum levels of different forms of sialic acid, Regan isoenzyme and lactase dehydrogenase. Int J Biol Markers 1991; 6: 177-182.