CXCL12 (stromal cell-derived factor, SDF-1), is an 8 kDa peptide chemokine. The interaction between CXCL12 and its receptor, CXCR4, plays a pivotal role in the trafficking of hematopoietic stem cells between bone marrow and peripheral blood. The CXCL12/CXCR4 axis may play a role in the pathogenesis of myeloid neoplasms. We developed a technique for the determination of intact (full length) CXCL12 and its protease(s)-induced truncation products in plasma from patients with myeloproliferative neoplasms (Cancer Res., 70, 3402, 2010). In the present work, we are extending our observations to the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CXCL12 concentrations in normal subjects were 16.6 ± 9.4 ng/mL (n=10). In primary myelofibrosis (PMF), the concentrations were 5.8 ± 4.0 ng/mL (n=15), and in polycythemia vera (PV) 7.9 ± 3.6 ng/mL (n=21). Now we report that in MDS/AML, the concentrations are 2.2 ± 2.1 ng/mL (n=8). In normal subjects, truncation products, due to proteolysis, were not detectable (≥ 1.0 ng/mL). The loss of 2, 3, 4, and 5 amino acids (aa) from CXCL12 were confirmed by molecular masses measured using electrospray ionization mass spectrometry. Quantification was completed with synthetic standards. In MDS/AML patients the concentration of the truncation product corresponding to −2 aa (KP removed),-3 aa (KPV removed), −4 aa (KPVS removed) and −5 aa (KPVSL removed) were 2.7 ± 3.2 ng/mL, 2.4 ± 2.1 ng/mL, 3.8 ± 3.0 ng/mL, and 2.5 ± 2.4 ng/mL, respectively. The total concentration of all truncation products was 11.3 ± 5.8 ng/mL. For comparison, the concentration of total truncation products was 28.7 ± 19.9 for PMF, and 31.1 ± 7.8 for PV. Patients with these myeloid malignancies have lower CXCL12 concentrations compared to normal controls and high concentrations of proteolytic truncation products which are absent in normal plasma. Of the 8 patients with MDS (n=3) and AML (n=5), treated with continuous infusion of ON 01910.Na (rigosertib), 650 - 1,700 mg/m2, in a Phase I dose escalation study, 4 patients attained a partial or complete bone marrow remission according to International Working Group criteria. The concentration of intact CXCL12 rose at 72 h in responding patients, whereas those who failed to respond had a decrease. These data suggest that monitoring intact CXCL12 and its truncation products may provide a marker of response to treatment with ON 01910.Na, as well as insight into the role of the CXCL12/CXCR4 axis in the pathobiology of these bone marrow diseases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2675. doi:1538-7445.AM2012-2675