The FLT3-ITD mutation and the expression of its downstream signaling intermediates STAT5 and Pim-1 are positively correlated with CXCR4 expression in patients with acute myeloid leukemia

Abstract

Chemokine ligand 12(CXCL12) mediates signaling through chemokine receptor 4(CXCR4), which is essential for the homing and maintenance of Hematopoietic stem cells (HSCs) in the bone marrow. FLT3-ITD mutations enhance cell migration toward CXCL12, providing a drug resistance mechanism underlying the poor effects of FLT3-ITD antagonists. However, the mechanism by which FLT3-ITD mutations regulate the CXCL12/CXCR4 axis remains unclear. We analyzed the relationship between CXCR4 expression and the FLT3-ITD mutation in 466 patients with de novo AML to clarify the effect of FLT3-ITD mutations on CXCR4 expression in patients with AML. Our results indicated a positive correlation between the FLT3-ITD mutant-type allelic ratio (FLT3-ITD MR) and the relative fluorescence intensity (RFI) of CXCR4 expression in patients with AML (r = 0.588, P ≤ 0.0001). Moreover, the levels of phospho(p)-STAT5, Pim-1 and CXCR4 proteins were positively correlated with the FLT3-ITD MR, and the mRNA levels of CXCR4 and Pim-1 which has been revealed as one of the first known target genes of STAT5, were upregulated with an increasing FLT3-ITD MR(P < 0.05). Therefore, FLT3-ITD mutations upregulate the expression of CXCR4 in patients with AML, and the downstream signaling intermediates STAT5 and Pim-1 are also involved in this phenomenon and subsequently contribute to chemotherapy resistance and disease relapse in patients with AML. However, the mechanism must be confirmed in further experiments. The combination of CXCR4 antagonists and FLT3 inhibitors may improve the sensitivity of AML cells to chemotherapy and overcome drug resistance.

Targeting CXCR4 in AML and ALL

“…Leukemic blasts with high CXCR4 expression in cases of AML was associated with higher rates of relapse and lower overall survival ( 25 – 35 ). Patients with a FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) or nucleophosmin mutation express significantly more CXCR4 than their wild-type counterparts ( 27 – 29 , 31 , 32 , 36 ). However, these cytogenetic abnormalities do not solely account for the elevated CXCR4 expression in the disease as high CXCR4 expression is still a risk factor for prognosis in normal karyotype patients with AML ( 29 , 30 ).…”

“…This is potentially due to the role CXCR4 plays in keeping leukemic cells within the bone marrow as well as its roles in activating pathways that favor the survival, growth, and chemotherapy resistance of these malignant cells (1). Leukemic blasts with high CXCR4 expression in cases of AML was associated with higher rates of relapse and lower overall survival (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Patients with a FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) or nucleophosmin mutation express significantly more CXCR4 than their wildtype counterparts (27-29, 31, 32, 36).…”

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

“…As the essential indicators in AML progression, there is an intimate connection between FLT3-ITD mutation and the CXCR4/CXCL12 axis with multiple interactions ( Fukuda et al, 2005 ). For example, FLT3-ITD mutation upregulates the expression levels of STAT5 (a regulatory factor for CXCR4 mRNA level), causing an increase in CXCR4 expression on the cell surface in AML ( Cao et al, 2019b ). Besides, LY2510924, a CXCR4 inhibition, could significantly increase the effect of FLT3 inhibitors in the AML cells with FLT3-ITD mutation ( Kim et al, 2020 ).…”

“…Chemokine ligand 12 (CXCL12), also named stromal-derived factor 1 (SDF-1α), can induce tumor cell migration in AML, and chemokine receptor 4 (CXCR4) is the specific receptor for CXCL12 ( Chatterjee et al, 2014 ). The signal pathways activated by the CXCL12/CXCR4 axis have been demonstrated to show effects in interactions between tumor cells and the microenvironment in AML, and the interactions would cause chemoresistance and AML relapse ( Lee et al, 2017 ; Cao et al, 2019b ). Several recent publications suggest an interaction between FLT3-ITD mutation and CXCL12/CXCR4 axis, and the CXCL12/CXCR4 axis has been proved an important role in the rapid emergence of resistance to FLT3 inhibitors ( Cao et al, 2019b ; Kim et al, 2020 ; Waldeck et al, 2020 ).…”

“…The signal pathways activated by the CXCL12/CXCR4 axis have been demonstrated to show effects in interactions between tumor cells and the microenvironment in AML, and the interactions would cause chemoresistance and AML relapse ( Lee et al, 2017 ; Cao et al, 2019b ). Several recent publications suggest an interaction between FLT3-ITD mutation and CXCL12/CXCR4 axis, and the CXCL12/CXCR4 axis has been proved an important role in the rapid emergence of resistance to FLT3 inhibitors ( Cao et al, 2019b ; Kim et al, 2020 ; Waldeck et al, 2020 ). Although it has been identified that the combination of the FLT3 inhibitor and CXCR4 antagonist could improve the sensitivity of chemotherapy treatment in AML cells ( Jacobi et al, 2010 ; Kim et al, 2020 ), the lack of understanding of the impact on AML cells produced by the interaction between FLT3-ITD mutation and the CXCL12/CXCR4 axis restricts the development of the related research.…”