Abstract
Patients suffering from acute myeloid leukemias (AML) bearing FMS-like tyrosine kinase-3-internal tandem duplications (FLT3-ITD) have poor outcomes following cytarabine- and anthracyclin-based induction therapy. To a major part this is attributed to drug resistance of FLT3-ITD-positive leukemic cells. Against this background, we have devised an antibody array approach to identify proteins, which are differentially expressed by hematopoietic cells in relation to activated FLT3 signaling. Selective upregulation of antiapoptotic myeloid cell leukemia-1 (MCL-1) was found in FLT3-ITD-positive cell lines and primary mononuclear cells from AML patients as compared with FLT3-wild-type controls. Upregulation of MCL-1 was dependent on FLT3 signaling as confirmed by its reversion upon pharmacological inhibition of FLT3 activity by the kinase inhibitor PKC412 as well as siRNA-mediated suppression of FLT3. Heterologously expressed MCL-1 substituted for FLT3 signaling by conferring resistance of hematopoietic cells to antileukemia drugs such as cytarabine and daunorubicin, and to the proapoptotic BH3 mimetic ABT-737. Conversely, suppression of endogenous MCL-1 by siRNA or by flavopiridol treatment sensitized FLT3-ITD-expressing hematopoietic cells to cytotoxic and targeted therapeutics. In conclusion, MCL-1 is an essential effector of FLT3-ITD-mediated drug resistance. Therapeutic targeting of MCL-1 is a promising strategy to overcome drug resistance in FLT3-ITD-positive AML.
Highlights
Activating mutation of the FMS-like tyrosine kinase-3 receptor (FLT3) occurs in 30 -- 40% of patients with acute myeloid leukemia (AML).[1,2] Two different types of mutations have been described: internal tandem duplications (ITD) within the juxtamembrane domain and tyrosine kinase domain 1, and point mutations within the tyrosine kinase domain 1.3 - 6 Both types of mutations cause constitutive activation of the FLT3 receptor resulting in constitutive downstream signaling via the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the phosphatidylinositol-3 kinase/AKT (PI3K/AKT) pathways
Based on the drug-resistant phenotype conferred by FLT3-ITD, we focused on proteins implied in the regulation of drug-induced apoptosis, such as the BCL-2 protein family.[35,36]
myeloid cell leukemia-1 (MCL-1) expression was found to be increased in FLT3-ITD-positive leukemic cell lines and primary AML blasts compared with FLT3 wild-type controls and was strictly dependent on FLT3 signaling as confirmed by its reversion upon pharmacological inhibition of FLT3 activity as well as siRNA-mediated suppression of FLT3
Summary
Activating mutation of the FMS-like tyrosine kinase-3 receptor (FLT3) occurs in 30 -- 40% of patients with acute myeloid leukemia (AML).[1,2] Two different types of mutations have been described: internal tandem duplications (ITD) within the juxtamembrane domain and tyrosine kinase domain 1, and point mutations within the tyrosine kinase domain 1.3 - 6 Both types of mutations cause constitutive activation of the FLT3 receptor resulting in constitutive downstream signaling via the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the phosphatidylinositol-3 kinase/AKT (PI3K/AKT) pathways. Targeting the aberrant FLT3-ITD receptor using specific tyrosine kinase inhibitors (TKIs) is a promising therapeutic approach.[13,14] Several small molecule TKIs targeting FLT3 have been investigated in phase 1/2 clinical trials
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