CXC Chemokine Receptor 4 Expression, CXC Chemokine Receptor 4 Activation, and Wild-Type Nucleophosmin Are Independently Associated With Unfavorable Prognosis in Patients With Acute Myeloid Leukemia

Abstract

BACKGROUND CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and is essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in AML patients and predicts a favorable prognosis. In vitro studies have suggested that mutant NPM decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways. PATIENTS AND METHODS In a group of 117 untreated adults with AML we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated (p) CXCR4 (pCXCR4) expression. All cases were also analyzed for NPM1 mutations using PCR-based methods. RESULTS CXCR4 expression was detected in 75 (64%) and pCXCR4 expression was detected in 31 (26%) patients. NPM1 mutations were detected in 63 (54%) patients. NPM1 mutations did not correlate with CXCR4 (p = 0.212) or pCXCR4 (p = 0.355) expression. The median 5-year overall survival was 27% (95% CI: 19-36%), with a median follow-up of 8 months (95%CI: 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematological disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival. CONCLUSION There is no correlation between NPM1 mutations and CXCR4 or phosphorylated CXCR4 expression suggesting that the CXCR4 and NPM pathways act independently in adult AML.

BETP degradation simultaneously targets acute myelogenous leukemic stem cells and the microenvironment

“…SLC7A11, a cystine-glutamate antiporter, is stabilized in the plasma membrane by CD44v8-10 through its interaction with and stabilization of X CT/SLC7A11 (27), while expression of Apart from transcription and protein translation, cell-surface expression of CXCR4 depends on its recycling and externalization on the cell membrane (33). PIM1-mediated phosphorylation of CXCR4 at S339 is necessary for its surface localization (34)(35)(36), and PIM1 is a known downstream target of BETP (37). Immunoblot analysis of OCI-AML3 cells treated with ARV-825 confirmed that PIM1 expression and the consequent phosphorylation of CXCR4 (S339) were decreased in the treated cells, while total CXCR4 protein expression remained unchanged ( Figure 3F).…”

Nitric oxide functions in stromal cell‑derived factor‑1‑induced cytoskeleton changes and the migration of Jurkat cells

“…Stromal cell-derived factor-1 (SDF-1) is a small chemokine that regulates the mobilization, retention, migration, trafficking and homing of hematopoietic stem cells and lymphocytes (10,11). An increasing amount of evidence has indicated that chemotaxis signaling serves a crucial role in the migration of cancer cells (12)(13)(14)(15). Chemokines serve roles as signal initiators and are involved in changes of the actin cytoskeleton (16), which are required for cellular morphological changes and motility (17).…”

Relationship between CXC chemokine receptor 4 expression and prognostic significance in acute myeloid leukemia

“…[21] In another study of 117 patients who were tested for NPM1 mutations by PCR, there was no correlation between CXCR4 expression and NPM1 mutation. [36] It has been reported that CXCR4 expression was significantly higher in FLT3-ITD AML than in FLT3/wt AML. [37] The possible mechanism was that FLT3-ITD may activate CXCR4 signaling, thereby further affecting the function of the SDF-1α/CXCR4 axis.…”