29 research outputs found
Anagrelide does not exert a myelodysplastic effect on megakaryopoiesis: a comparative immunohistochemical and morphometric study with hydroxyurea
A comparative immunohistochemical and
morphometric study was performed on megakaryocytes
in 20 patients presenting with initial-early stage chronic
idiopathic myelofibrosis and accompanying
thrombocythemia to elucidate histological features
developing after hydroxyurea (HU) versus anagrelide
(ANA) therapy. Representative pre-and posttreatment
bone marrow biopsies were involved including the
monoclonal antibody CD61 for the identification of
precursor and mature stages of megakaryopoiesis. An
elaborate morphometric evaluation was in keeping with
a left-shifting showing a more frequent occurrence of
promegakaryoblasts and microforms in both therapy
groups. However, contrasting ANA, HU generated
defects of differentiation consistent with significant
dysplastic changes. In conclusion, concern about a
possible leukemogenic capacity following long-term HU
therapy is supported by our findings
Therapy-related changes of the bone marrow in chronic idiopathic myelofibrosis
In chronic myeloproliferative disorders
(CMPDs) a conflict of opinion exists regarding therapyinduced
bone marrow (BM) changes and the evolution
of myelofibrosis during the lengthy course of the
disease. For a more elaborate study of these features
chronic idiopathic myelofibrosis (IMF) seems to be a
most suitable condition. Therefore this review is focused
on this CMPD and amongst other findings analyzes data
from a series of 340 patients with a long follow-up
including 893 biopsies (median interval of 32 months).
The ensuing results were compared with those
communicated in the relevant literature. In addition to a
control group of 153 patients with IMF who received
only symptomatic treatment, therapy groups included
busulfan, hydroxyurea, interferon and various
combinations. In all groups hypoplasia of a varying
degree was a frequent finding (6%) and often
accompanied by a patchy arrangement of hematopoiesis.
Most conspicuous was a gelatinous edema showing a
tendency to develop a discrete reticulin fibrosis
(scleredema). Aplasia developed in 7.7% of patients,
usually at terminal stages of the disease independently of
treatment. Minimal to moderate maturation defects of
hematopoiesis involved especially megakaryocytes and
erythroid precursors, but overt myelodysplastic features
were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were
characterized not only by increasing dysplastic changes,
but also by the appearence of blasts including CD34+
cells. Semiquantitative grading of the fiber content
revealed that 183 patients (54%) without or with
moderate fibrosis at the beginning showed a significant
progression and therefore contrasted with the 66 patients
with a stable state. Following this calculation no relevant
differences in the evolution of myelofibrosis were
evident in the various therapy groups especially not
following interferon treatment. In a few patients a
regression was found which was accompanied by a severe hypoplasia or aplasia compatible with a myeloablative
effect. In conclusion, peculiar BM changes, in
particular conspicuously expressed myelodysplastic
features are consistent with therapy-related lesions.
Development of myelofibrosis in IMF is obviously due
to disease progression unrelated to stage at diagnosis and
not significantly influenced by treatment modalities
Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons
The puromycin-sensitive aminopeptidase (PSA) is thought to contribute to the degradation of enkephalins. Besides being the most abundant aminopeptidase in the brain, PSA is expressed in other organs as well. From a human fetal brain cDNA library, we have isolated a cDNA encoding the human PSA (huPSA) protein. The isolated cDNA gave rise to a protein with a molecular mass of 99 kDa. Compared with mouse PSA, homology at the amino acid and cDNA level was 98 and 93%, respectively. Translation of the huPSA was found to be initiated at the second of two possible start codons, as shown by studies with antibodies directed against peptide sequences of both potential N-terminal regions. Northern blot analysis with RNA isolated from different human organs demonstrated that the huPSA transcript is strongest but not exclusively expressed in the brain. Vesicular stomatitis virus epitope-tagged huPSA protein was expressed in HeLa cells and found to be localized in the cytoplasm, especially in the perinuclear region. By in situ hybridization, huPSA transcript could be identified in cortical and cerebellar neurons, whereas glial cells and blood vessels remained negative
Effects of the tyrosine kinase inhibitor Imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia
Preliminary data are available about bone
marrow (BM) changes in patients with chronic myeloid
leukemia (CML) who received the molecularly targeted
and highly effective tyrosine kinase inhibitor Imatinib
mesylate (STI571). This review is focused on a
systematic assessment of BM features detectable at
different stages of CML (stable, accelerated, blastic)
following long-term (more than 10 months) treatment.
By applying enzyme- and immunohistochemistry
including monoclonal antibodies visualizing
proliferating cell nuclear antigen (PCNA) and apoptosis
(anti-apostatin), a more elaborate insight into alterations
affecting hematopoiesis and the stroma compartment
was gained. In patients with stable-phase CML therapy
resulted in a significant reduction in cellularity,
neutrophil granulopoiesis and number of
megakaryocytes, accompanied by a retrieval of erythroid
precursors. In patients with Imatinib as the only
treatment morphometric analysis of CD61+
megakaryopoiesis was in keeping with a significant
decrease in maturation defects implying a lesser amount
of atypical micromegakaryocytes almost consistent with
normalization. Moreover, a reduction of the initially
enhanced (CD34+) microvessel density was detectable
associated with a decrease in luminal distension.
Regression of marked to moderate myelofibrosis was
recognizable in about 70% of patients especially in the
accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozymeexpressing
immature myelomonocytic cells declined
with treatment, but recurred in about 19% of patients
that developed a leukemic relapse after 21±6 months of
therapy. Data on proliferative activity and apoptosis in
general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with
a tendency for stimulated apoptosis, at least in
responding patients