Leopold Oehler

Comorbidity predicts survival in myelodysplastic syndromes or secondary acute myeloid leukaemia after allogeneic stem cell transplantation.

Background  Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT).

Interleukin-10 inhibits burst-forming unit-erythroid growth by suppression of endogenous granulocyte-macrophage colony-stimulating factor production from T cells

Numerous cytokines released from accessory cells have been shown to exert either stimulatory or inhibitory growth signals on burst-forming unit-erythroid (BFU-E) growth. Because of its cytokine synthesis-inhibiting effects on T cells and monocytes, interleukin-10 (IL-10) may be a potential candidate for indirectly affecting erythropoiesis. We investigated the effects of IL-10 on BFU-E growth from normal human peripheral blood mononuclear cells (PBMC) using a clonogenic progenitor cell assay. The addition of recombinant human IL-10 to cultures containing recombinant human erythropoietin suppressed BFU-E growth in a dose-dependent manner (by 55.2%, range 47.3-63.3%, p < 0.01, at 10 ng/mL). In contrast, no inhibitory effect of IL-10 was seen when cultivating highly enriched CD34+ cells. BFU-E growth from PBMC also was markedly suppressed in the presence of a neutralizing anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (by 48.7%, range 32.9-61.2% inhibition,p < 0.01), but not by neutralizing antibodies against granulocyte colony-stimulating factor and interleukin-3. This suggests a stimulatory role of endogenously released GM-CSF on BFU-E formation. Also, the addition of exogenous GM-CSF completely restored IL-10-induced suppression of BFU-E growth. To determine the cellular source of GM-CSF production, we analyzed GM-CSF levels in suspension cultures containing PBMC that were either depleted of monocytes or T cells. Monocyte-depleted PBMC showed spontaneous production of increasing amounts of GM-CSF on days 3, 5, and 7, respectively, which could be suppressed by IL-10, whereas GM-CSF levels did not increase in cultures containing T-cell-depleted PBMC. Our data indicate that IL-10 inhibits the growth of erythroid progenitor cells in vitro, most likely by suppression of endogenous GM-CSF production from T cells.

In vivo effects of imatinib mesylate on human haematopoietic progenitor cells

Background  Imatinib mesylate has considerable antineoplastic activity in patients with chronic myeloid leukaemia (CML) and some solid tumours. Although originally regarded as nontoxic for normal haematopoiesis, mild to moderate myelosuppression is a commonly observed side‐effect of this treatment. Recently, this molecule has been shown to suppress normal haematopoietic progenitor cells in vitro. This is the first study that has investigated the effect of imatinib on haematopoietic progenitor cells in vivo.

Dasatinib inhibits progenitor cell proliferation from polycythaemia vera

Background  A mutation of Janus kinase 2 V617F is present in most patients with polycythaemia vera (PV). However, it is generally believed that JAK2V617F is not the sole molecular abnormality in PV. Since dasatinib is currently evaluated in patients with PV, it is of interest to study the effects of dasatinib on the growth of clonal progenitor cells in vitro.

The JAK2V617F mutation: no impact on circulating hematopoietic progenitors in myeloproliferative disorders.

Dear Editor, The recently discovered gain of function mutation in the pseudokinase domain of JAK2, JAK2, is frequently found in Philadelphia chromosome-negative myeloproliferative disorders (Ph MPDs) [1]. This point mutation is found in the vast majority of patients with polycythemia vera (PV) and in 30% to 60% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Myeloproliferative disorders with a non-mutated JAK2 (JAK2 wild type) may underlie a different molecular abnormality. This may result in a different proliferative capacity of the clonal hematopoietic progenitor cells, both in vivo and in vitro. Increased numbers of hematopoietic progenitor cells in peripheral blood of patients is a characteristic feature in patients with MPDs and is especially pronounced in IMF [3]. Hematopoietic precursor cells of patients with MPDs may exhibit endogenous erythroid colony growth in vitro. We studied the numbers of circulating hematopoietic progenitor cells in a large group of Ph MPD patients who harbored or did not harbor the mutated JAK2 gene. Peripheral blood samples were collected from 72 patients with PV (30 women), 65 patients with ET (37 women), 23 patients with IMF (ten women), and ten patients with Ph chronic myeloid leukemia (five women) at diagnosis. The study was approved by the institutional review board, and informed consent was obtained from all patients. Diagnosis was established according to the World Health Organization criteria. Median age at diagnosis was 58 years in PV patients (range 30–89 years), 55 years in ET patients (range 28–80 years), and 60 years in IMF patients (range 45– 80 years). Peripheral blood progenitor cells were also assessed in 62 healthy subjects who served as a control group. The control group was not matched for sex and age. The number of circulating hematopoietic progenitor cells was determined at diagnosis according to our standard protocol as described [4]. All patients were tested for the presence of the JAK2 mutation as described [1]. Hematopoietic progenitor cells are described by median and range and are compared by the Mann–Whitney U test. Blood counts are given by mean values and standard deviation and are evaluated for significance using Student t test of unpaired data. The median age of all Philadelphia chromosome-negative (Ph) MPDs was 58 years at diagnosis. Seventy-seven patients (48%) were women and 83 patients (52%) were men. In the 160 Ph MPD patients analyzed, the presence or absence of the JAK2 mutation did not correlate with age at diagnosis or gender (data not shown). Complete blood counts were obtained from all patients at diagnosis. The presence of the JAK2 mutation did not influence peripheral blood counts of patients with PV and IMF. Significantly lower platelet numbers were found in patients with ET who had this mutation (JAK2 735×10/L±42; JAK2 951×10/L±90, p=0.017), whereas hemoglobin level and white blood counts were not significantly affected by the JAK2 mutation status. This is in keeping with previous reported findings showing Ann Hematol (2008) 87:509–511 DOI 10.1007/s00277-007-0428-x