Page 202 - Haematologica Vol. 109 - July 2024

ARTICLE - FLT3L promotes osteolysis in multiple myeloma
FLT3L-DKK1 pathway. In summary, a network model (Online Supplementary Figure S6) shows that FLT3L binds to its receptor FLT3, and FLT3 then activates STAT3 signaling to induce DKK1, which inhibits WNT signaling to decrease its target genes involved in bone formation.
Discussion
Osteolytic bone lesions greatly diminish the QoL for ad- vanced MM patients. Unfortunately, the molecular mech- anisms underlying the development of these bone lesions have not yet been determined, which poses a challenge for the development of effective therapeutic strategies. In this study, we aimed to address this knowledge gap by examining plasma samples derived from the BM of 86 MM patients, 306 AML patients, and 52 ALL patients. Our investigation revealed that the expression of FLT3L in MM patients was significantly higher compared to AML and ALL patients. Notably, elevated FLT3L levels were found to be positively correlated with a poorer prognosis in MM patients. In vitro analysis demonstrated that FLT3L-mediated STAT signaling pathways contribute to the upregulation of DKK1 expression, a soluble antagonist for the WNT signal cascade. Given the role of WNT signaling in osteoblastic differentiation, these findings suggest that the FLT3L-STAT3-DKK1 axis is involved in the development of osteolytic bone lesions in MM patients. Furthermore, our analysis of previously col- lected transcriptome data revealed that the activation of the FLT3L-STAT3-DKK1 pathway predominantly occurs in the HY subtype of MM. This finding holds significant promise for improving the accuracy of bone osteolysis prediction and treatment, as it provides a potential diagnostic marker to identify the involvement of the FLT3L-STAT3-DKK1 pathway. Taken together, these findings provide novel insights into the molecular mechanisms underlying osteolytic bone le- sions in MM patients. By uncovering the FLT3L-STAT3-DKK1 axis as a key pathway, these studies shed light on the new opportunities for the diagnosis of MM and the development of potential therapeutic interventions for MM patients. Hyperdiploidy has been seen to be a good prognostic factor in MM,39,40 while, in our study, high FLT3L was associated with osteolytic bone lesion and poor survival. To explore the relationship between FLT3L, HY, and FLT3L-DKK1-mediated bone osteolysis, we performed multivariate logistic regres- sion analysis. In this analysis, FLT3L served as a dependent variable, while clinical factors including HY and osteolytic bone lesions were treated as independent variables. We no- ticed that FLT3L was not only associated with hyperdiploidy, which is known as a good prognostic factor (P=0.044), but also associated with plasma cell fraction in BM, a surrogate marker of disease stage (P=0.029) (Online Supplementary Table S1). These findings may appear inconsistent with the claim in the current study that HY-MM subtype presumably represented FLT3L-DKK1 pathway-mediated pathological
D. Shin et al. features, leading to subsequent deterioration in the QoL of
the affected patients. However, recent studies have revealed that even among patients with the HY-MM subtype there is a considerable cytogenetic heterogeneity, resulting in distinct clinical outcomes and diverse prognoses.39,41,42 Indeed, in our study, the enrichment of the FLT3LHDKK1H group among HY- MM subtype patients led to discernible differences in tran- scriptomic profiles compared to the other HY-MM patients (Figure 4F). Therefore, detailed functional relationships of FLT3L-DKK1 pathway with the previously established MM subtypes, along with its potential use as biomarkers for MM prognosis prediction, still have to be clarified.
Phase III randomized clinical trials proved that pamidronate and zoledronate, the 2 most commonly used bisphos- phonates in the clinic, reduce bone osteolysis in MM.28,43 However, the prolonged use of these bisphosphonates can cause the serious complication of bisphosphonate-related osteonecrosis of jaw (BRONJ) or subtrochanteric femoral insufficiency.44,45 Although denosumab, a RANKL inhibitor recently approved for bone-directed adjunctive therapy for MM, was proven to be more effective than the bisphospho- nates,46 the side effect of BRONJ has also been reported in patients treated with denosumab. The addition of bis- phosphonate46,47 or RANKL-targeted monoclonal antibody to the standard chemotherapy regimens can lessen bone resorption by suppressing osteoclastic activity, but these agents cannot fully inhibit the progression of the bone os- teolytic process. Furthermore, the recovery of osteolytic lesions during treatment is rarely observed, which means that the current strategy to target osteoclastic activity in MM patients with bone involvement has still not been suc- cessfully achieved. Thus, it is important to develop alter- native or complementary therapies that can target reduced osteoblastic activity that can, therefore, be used together with existing therapeutic options to improve the treatment of bone osteolysis in patients with MM.
New effective bone-directed therapeutic strategies need to be developed to overcome the adverse effect of the current standard therapies and improve MM patients’ QoL. Targeting the FLT3L-STAT3-DKK1 pathway that primarily reduces the osteoblastic activity via suppression of WNT signaling might be a promising therapeutic approach because it can restore the reduced osteoblastic activity. Inhibition of FLT3L can thus provide a complementary therapeutic axis to the existing bisphosphonates and RANKL inhibitors that mainly target the osteoclastic activity. Targeting both osteoblastic and osteoclastic activities using a combined therapy of FLT3L/ FLT3 inhibitors,48 bisphosphonates, RANKL inhibitor and/or the standard chemotherapy are expected to effectively im- prove therapeutic outcomes for MM patients with osteolytic bone lesions. As a downstream regulator of FLT3 signaling, DKK1 induces inhibition of WNT signaling in osteoblastic differentiation in MM.49 DKK1 inhibitors have been proposed as a promising therapeutic strategy to target the reduced osteoblastic activity in MM. The benefits and disadvantag-
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