Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients.

Early treatment of CLL/SLL does not impact survival-reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic-based prognostic model. Fifty-nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL-10, IL-5, sIL-2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL-17, IL-23, IFN-γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL-2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow-up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL-17/sIL-2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy.

Bone Marrow and Peripheral Blood AML Cells Are Highly Sensitive to CNDAC, the Active Form of Sapacitabine.

Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3-6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shown in vivo activity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.

CD26 protease inhibition improves functional response of unfractionated cord blood, bone marrow, and mobilized peripheral blood cells to CXCL12/SDF-1.

Hematopoietic stem cell transplantation (HSCT) is an important treatment option for patients with malignant and nonmalignant hematologic diseases. Methods to improve transplant efficiency are being explored with the intent to improve engraftment and immune reconstitution post-HSCT. A current approach under investigation involves treatment of donor cells with inhibitors that target the protease CD26, a negative regulator of the chemokine CXCL12/stromal cell-derived factor-1. CD26 inhibitor treatment has been shown to improve the functional response of CD34(+) cord blood (CB) cells, but not CD34(+) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, to CXCL12/stromal cell-derived factor-1. The effect of CD26 inhibitors on unfractionated CB, bone marrow, or granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells has not been evaluated previously. We observed that although CB had greater CD26 expression than bone marrow or mobilized peripheral blood, treatment with a CD26 inhibitor (Diprotin A) resulted in increased responsiveness to stromal cell-derived factor-1 for all three mononuclear cell sources tested. This suggests that clinical therapeutic benefit might be gained by using CD26 inhibitors as a strategy to improve engraftment of unfractionated mobilized peripheral blood cells as well as CB cells.

In vivo expansion of the megakaryocyte progenitor cell population in adult CD26-deficient mice.

OBJECTIVE: Megakaryopoiesis involves commitment of hematopoietic stem cells (HSC) toward the myeloid lineage in combination with the proliferation, maturation, and terminal differentiation of progenitors into megakaryocytes. The exact mechanism of megakaryocyte development from HSC is unknown, but growth factors such as thrombopoietin have been identified as critical. Additionally, it has been suggested that the chemokine CXCL12/stromal-cell derived factor-1α has a role in regulating megakaryopoiesis and thrombopoiesis. We recently reported the importance of the extracellular protease CD26 (dipeptidylpeptidase IV) in regulating HSC responses to CXCL12, as well as modulating HSC trafficking into and out of the bone marrow. However, the importance of CD26 for megakaryopoiesis has not been reported. We therefore compared megakaryocyte development between CD26-deficient (CD26(-/-)) mice and C57BL/6 control mice. MATERIALS AND METHODS: Adult CD26(-/-) mice and C57BL/6 control mice were evaluated using blood differentials, histological analysis, flow cytometric analysis, and progenitor colony assays. RESULTS: Bone marrow from CD26(-/-) mice has a significantly expanded megakaryocyte and megakaryocyte progenitor population compared to control C57BL/6 mice bone marrow. CONCLUSIONS: Our results indicate that endogenous CD26 normally suppresses megakaryopoiesis and that loss of CD26 activity results in expansion of the megakaryocyte progenitor population in vivo. This suggests the potential use of CD26 inhibitors to improve megakaryocyte progenitor function and/or reconstitution of the megakaryocyte cell population.