Abstract
Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD) are detected in 10–15% of children and 30% of adult patients with AML and are associated with an extremely poor prognosis. Although several antagonists against FLT3/ITD have been developed, few of them are effective for the treatment of FLT3/ITD+ AML because of the emergence of drug-resistant cells. The mechanisms responsible for drug resistance include the acquisition of additional mutations in the FLT3 gene and/or activation of other prosurvival pathways such as microenvironment-mediated resistance. Recent studies have strongly suggested that the reciprocal interaction between the microenvironment and AML cells generates specific machinery that leads to chemoresistance. This chapter describes the molecular mechanism responsible for the refractory phenotype of FLT3/ITD+ AML cells resulting from the communication between the microenvironment and FLT3/ITD+ leukemia cells. Understanding this mechanism enables the discovery of novel and innovative therapeutic interventions for resistant FLT3/ITD+ AML.
Keywords
- FLT3/ITD
- microenvironment
- niche
- drug resistance
- CXCL12/CXCR4
1. Introduction
Mutations in the FLT3 gene represent the most common genetic aberrations among patients with acute myeloid leukemia (AML) [1, 2]. Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD), which are expressed in human acute myeloid leukemia (AML) stem cells, are found in ~30% of patients with AML [3]. FLT3/ITD+ AML is one of the most intractable hematological malignancies because of the emergence of resistant clones to FLT3/ITD inhibitors or chemotherapies [3, 4]. FLT3/ITD allows ligand-independent activation and phosphorylation of the FLT3 receptor. Ectopic FLT3/ITD expression in IL-3–dependent mouse Ba/F3 or 32D hematopoietic cells results in growth factor–independent proliferation and produces acute leukemia in mice [5, 6]. Studies have indicated that FLT3/ITD transforms mouse hematopoietic cell lines via the activation of the
Human AML stem cells residing in the endosteal niche of the bone marrow are relatively chemoresistant [30, 31]. This resistance results from survival cues in the form of various cytokines and adhesion molecules provided by niche cells [32]. Studies using the FLT3/ITD inhibitors have demonstrated that FLT3/ITD+ AML blasts circulating in the peripheral circulation were very sensitive to these inhibitors, whereas those residing in the marrow endosteal region remained resistant to the FLT3/ITD inhibitor [33]. Reports have demonstrated that stromal cells protect FLT3/ITD AML cells from apoptosis induced by FLT3/ITD inhibitors [34, 35, 36]. These studies suggest that leukemia niches provide survival cues that protect FLT3/ITD+ AML blasts from being eradicated by the FLT3/ITD inhibitors. In agreement with these observations, early study demonstrated that releasing leukemia cells from the marrow niche into the peripheral circulation by blocking the
2. Microenvironmetal factors inducing the resistance of FLT3/ITD+ AML cells to FLT3 inhibitors
2.1. CXCL12/CXCR4 signaling pathways as a mechanism responsible for the resistance of FLT3/ITD AML cells to the FLT3 inhibitor
One of the machineries that holds AML cells in the bone marrow microenvironment is the interaction between
Although reports have indicated that
2.2. Cytokine signaling in the microenvironment as salvation factors for FLT3/ITD+ AML
2.3. STAT3/SURVIVIN signaling pathways
2.4. ERK/MAPK signaling pathways
An additional mechanism responsible for the resistance to the
2.5. Cyclin-dependent kinase inhibitor 1a/Pbx1 signaling pathways
The report by Yang et al. also noted the cell cycle arrest of FLT3/ITD+ AML cells cocultured by stromal cells [36], indicating that stromal cells provide factors that induce cell cycle quiescence.
2.6. RUNX1 in the resistance of FLT3/ITD+ AML
A recent report demonstrated that FLT3/ITD signaling is associated with a common expression signature as well as a common chromatin signature. The study identified that FLT3/ITD induces the chronic activation of
2.7. FLT3/ITD evades external inhibitory cytokine control
While it has been unclear how leukemia cells escape from normal cytokine control that is indispensable to maintain normal hematopoiesis, a recent study demonstrated that FLT3/ITD facilitates the development of myeloproliferative disease by inhibiting the interferon response [20, 26]. Interferon exhibits an anti-proliferative effect on primitive hematopoietic cells [83, 84, 85, 86], including FLT3/ITD+ cells [20]. In FLT3/ITD+ cells, activated STAT5 up-regulates SOCS1 expression, which inhibits the antiproliferative effect induced by interferon-α or interferon-γ [20]. SOCS1 protects FLT3/ITD+AML cells from external interferon control, thereby promoting myeloproliferative disease. Another report also uncovered a novel mechanism responsible for the escape of FLT3/ITD+ AML cells from interferon signaling. Micro-RNA 155 (miR-155) is significantly overexpressed in FLT3/ITD AML [87, 88, 89, 90, 91, 92] and promotes myeloproliferative disease induced by FLT3/ITD. This was coincided with repression of the interferon response compared with that with wild-type FLT3. Inhibition of miR-155 resulted in the elevation of the interferon response and reduction in the proliferation of human FLT3/ITD+ AML cells. The data indicate that miR-155 promotes FLT3/ITD+ AML cell proliferation by blocking interferon signaling [26]. Taken together, FLT3/ITD stimulates AML cell proliferation by evading external antiproliferative cytokine control that is normally provided by the microenvironment (Figure 1). It remains to be determined if these mechanisms are involved in the resistance against
FLT3/ITD+ AML is also found in patients with acute promyelocytic leukemia who harbor the PML-RARα fusion gene resulting from chromosomal translocation. Recent data have demonstrated that the combination of the FLT3/ITD inhibitor and ATRA, which targets PML-RARα, displays a synergistic effect of reducing the burden of FLT3/ITD+ AML both
2.8. Interaction of FLT3/ITD+ AML cells with the microenvironment via adhesion molecules
The interaction between AML cells and the microenvironment is mediated by various factors, such as
Taken together, these data provide evidence that stromal cells, or other cells comprising the microenvironment, support FLT3/ITD+AML cells via soluble factors and adhesion molecules, which, in turn, activate survival or proliferative signaling in the AML cells (Figure 1). However, the machinery provided by the microenvironment is not confined to these factors described above. A recent report has indicated that bone marrow mesenchymal stromal cells transfer their mitochondria to AML cells to support their proliferation [104, 105], possibly representing an additional mechanism that can enhance the resistance to the
3. Functional interaction between FLT3/ITD and CXCR4 in the migration and homing of AML cells that are associated with resistance
Because
Although the
An additional molecular machinery that specifically mediates the migration of FLT3/ITD+ cells is
4. Effect of FLT3 mutation on the microenvironment
Normal hematopoietic stem cells drive hematopoiesis, but this process requires appropriate factors secreted by adjacent cells, adhesion molecules, neighboring cells such as mesenchymal stromal cells, osteolineage cells, and endothelial cells that exist in the microenvironment [113]. In agreement with the microenvironment mediating the tight control necessary for normal hematopoiesis, earlier studies have demonstrated that malfunction of microenvironmental cells can lead to the development of myeloproliferation, which represents one of the outcomes of aberrant hematopoiesis. Walkley et al. demonstrated that the loss of retinoic acid receptor gamma (PARγ) resulted in myeloproliferation in mice; however, the transplantation of the marrow cells into PARγ-deficient cells did not cause myeloproliferation in wild-type recipients, whereas the transplantation of wild-type marrow cells caused myeloproliferation in PARγ-deficient recipients, indicating that myeloproliferation caused by the loss of PARγ was microenvironmental [114]. The microenvironmental effect on aberrant myeloproliferation is also supported by experiments using Rb-deficient cells. Knocking out Rb resulted in myeloproliferation in mice; however, the genetic defect in both hematopoietic cells and the microenvironment was necessary for the development of myeloproliferation [115]. Furthermore, deletion of DICER1 in primitive osteolineage cells led to myelodysplastic syndrome and AML [116], indicating that malfunction of
Reports have demonstrated that HSCs regulate their own niches by instructing neighboring stromal cells to produce supportive factors or alter the overall microenvironment [117, 118, 119]. While the marrow niche supports leukemia cell proliferation or protects cells from chemotherapeutic insult by providing various survival signals, recent evidence has demonstrated that leukemia cells modulate the marrow environment to create a supportive niche favoring survival for AML cells, just as healthy HSCs regulate their niche. Zhang et al. demonstrated that chronic myeloid leukemia (CML) cells modulate the microenvironment in favor of CML cells over healthy HCS by modulating
5. Summary
FLT3/ITD+ AML can become refractory to
Acknowledgments
The authors declare that no potential conflicts of interest associated with this study exist. This work was supported by research support funds from the Grant-in-Aid for Scientific Research (17K10111 to S.F.) and a Grant-in-Aid for Young Investigators (15K19616 to T.H.) from the Japanese Society for the Promotion of Science.
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