Importance of PTM of FLT3 in acute myeloid leukemia

Abstract

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoietic cells. Internal-tandem duplication domain (ITD) mutation and tyrosine kinase domain (TKD) mutation are the two most common mutations in acute myeloid leukemia (AML). Post-translational modifications (PTMs) of FLT3, such as glycosylation and ubiquitination, have been shown to impact various aspects of the protein in both wild-type (WT) and mutant forms of FLT3. In this review, we describe how the glycosylation status of FLT3 affects its subcellular localization, which significantly impacts the activation of downstream signaling, and the impact of specific ubiquitination on FLT3 function and stability, which may be associated with disease progression. Moreover, potential novel therapeutic strategies involving a combination of FLT3 tyrosine kinase inhibitors and drugs targeting glycosylation or ubiquitination are discussed.

1. Introduction

Acute myeloid leukemia (AML) is a hematological malignancy originated from hematopoietic stem cells [1]. While relatively uncommon, comprising only 1% of all cancer diagnoses, AML is the predominant form of leukemia in the adult population [2]. The estimated 5-year overall survival rate is 30%, exhibiting significant variation across age groups, reaching 50% in younger patients and decreasing to below 10% in patients older than 60 years [3]. Several risk factors, including myelodysplastic syndrome (MDS), myeloproliferative disease, environmental exposures, and genetic predispositions, play a role in the pathogenesis of AML [2]. It is characterized by the clonal expansion of immature myeloid blast cells in the peripheral blood and bone marrow, leading to ineffective erythropoiesis and bone marrow failure [4]. With recent advancements in management guidelines, the overall cure rate has improved in younger patients. Although therapeutic regimens have advanced, the prognosis for the elderly population remains poor [5].

Mutations in genes involved in hematopoiesis are a significant feature of AML. Among them, FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in AML [6]. The FLT3 protein belongs to the type III receptor tyrosine kinase (RTK) family, which is exclusively expressed in normal bone marrow stem/progenitor cells [7]. FLT3 is activated by binding of the FLT3 ligand (FL). Following activation, homodimers are assembled in the plasma membrane, resulting in receptor autophosphorylation. Activated FLT3 phosphorylates various effector molecules involved in the proliferation, differentiation, and apoptosis of hematopoietic cells. Approximately 30% of AML patients harbor constitutively activating mutations in the FLT3 gene, mostly internal tandem duplications (ITDs), which represent the insertion of nucleotide sequences of different lengths and at different sites [8]. The other predominant point mutation is the tyrosine kinase domain (TKD) mutation [9]. Papaemmanuil et al. [6] conducted a comprehensive study involving 1540 patients diagnosed with AML and reported the presence of FLT3 mutations in more than 500 patients. Christian et al. [10] performed a study involving 1485 patients diagnosed with AML and reported that the frequency of FLT3-ITD mutations was 312 of 1485 (21%). Bacher et al. [11] analyzed the mutational status and clinical significance of FLT3-TKD. They investigated 3082 patients with AML and observed FLT3-TKD mutations in 147 patients (4.8%). Furthermore, Ozeki et al. [12] reported that even in patients with wild-type (WT) FLT3, a discernible increase in overall survival was found in patients with high FLT3 expression (5 of 86 patients without FLT3-ITD mutations).