FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Abstract

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

TIFAB accelerates MLL-AF9−Induced acute myeloid leukemia through upregulation of HOXA9

“…To investigate the underlying molecular mechanism whereby TIFAB enhances leukemogenesis, we performed RNA-sequencing (RNA-seq) using FACS-sorted control or TIFAB-transduced leukemic stem cells (Lin lo/- Sca1 − CD117 + CD16 + CD34 + ) from mice with full-blown leukemia. Compared to control LSCs, TIFAB LSCs showed downregulation of genes related to myeloid differentiation (Cd14, Cd163, Mpo, Elane, Csf1r) and cell cycle inhibition (Cdkn2a), whereas upregulated genes related to maintenance of the LSC signature ( Six1 , Msi2 , Flt3, and Hoxa gene families) ( Calvo et al., 2000 ; Chu et al., 2019 ; Collins and Hess, 2016 ; Ito et al., 2010 ; Kennedy and Smith, 2020 ) ( Figure 3 A). The upregulation of FLT3 also contributes to TIFAB's leukemia-enhancing impact, given that FLT3 is commonly mutated (approximately one-third of newly diagnosed AML) and associated with increased relapse and inferior overall survival ( Kennedy and Smith, 2020 ).…”

“…Compared to control LSCs, TIFAB LSCs showed downregulation of genes related to myeloid differentiation (Cd14, Cd163, Mpo, Elane, Csf1r) and cell cycle inhibition (Cdkn2a), whereas upregulated genes related to maintenance of the LSC signature ( Six1 , Msi2 , Flt3, and Hoxa gene families) ( Calvo et al., 2000 ; Chu et al., 2019 ; Collins and Hess, 2016 ; Ito et al., 2010 ; Kennedy and Smith, 2020 ) ( Figure 3 A). The upregulation of FLT3 also contributes to TIFAB's leukemia-enhancing impact, given that FLT3 is commonly mutated (approximately one-third of newly diagnosed AML) and associated with increased relapse and inferior overall survival ( Kennedy and Smith, 2020 ). The upregulation of Hoxa cluster genes was further validated by quantitative RT-PCR analysis ( Figure 3 B).…”

Autophagy and Metabolism in Normal and Malignant Hematopoiesis

“…These increased ROS levels were shown to promote AML blast proliferation [165]. Activating mutations of the FLT3 receptor are detected in approximately one third of newly diagnosed AML cases, with ITD mutations being associated with an adverse prognosis [166]. The increased levels of endogenous ROS demonstrated in FLT3-ITD-mutated AML could be associated with the aggressiveness and poor prognosis of these AML cases [167].…”

Targeted Therapies for the Evolving Molecular Landscape of Acute Myeloid Leukemia

“…Two well-defined activating mutations hold clinical relevance: the FLT3 Internal Tandem Duplicate (ITD) and FLT3 tyrosine kinase domain (TKD) point mutation. FLT3 ITD mutations are among the most common mutations in AML, comprising about 25% of cases, and point mutations in the FLT3 TKD (D835 or I836) make up 5–10% of cases [ 39 ]. While the exact prognostic significance of FLT3 TKD mutant AML remains unclear, because this class of disease as a whole portends poorer outcomes, the development of potent tyrosine kinase inhibitors quickly emerged as an area of medical necessity.…”