Konference: 2006 48th ASH Annual Meeting - účast ČR
Kategorie:
Myelodysplastický syndrom
Téma: Poster session: Myelodysplastic Syndromes: Molecular Biology
Číslo abstraktu: 2634
Autoři: prof. MUDr. Jaroslav Čermák, CSc.; MUDr. Soňa Peková, Ph.D.; MUDr. Iuri Marinov, CSc.; MUDr. Dana Mikulenková
An acquired somatic mutation of PIG-A gene leads to a deficiency in
glycosyl phosphatidyl inositol-anchored proteins (GPI-APs) in
affected cells. A typical clinical manifestation of the GPI-APs
deficiency is paroxysmal nocturnal hemoglobinuria (PNH) with
intravascular hemolysis, various degree of cytopenia reflecting
marrow failure and trombophilia. Besides so-called "classic" PNH,
clinical and laboratory features of PNH may also be present in some
patients with aplastic anemia (AA) or myelodysplasia (MDS).
Moreover, a small subset of AA or MDS patients may exhibit in
peripheral blood small populations of GPI-APs deficient red blood
cells (RBC) and granulocytes, not accompanied by clinical and
laboratory signs of hemolysis. This subset of patients with a small
PNH clone may respond to immunosuppressive therapy. Herein, we
report on three patients who were referred to our hospital with the
diagnosis of unclassified MDS (RA unclassifiable according to the
WHO classification). In all patients, bone marrow aspiration and
biopsy revealed normocellular marrow with only minimal to mild
dysplasia with no excess of blasts and no karyotype abnormalities.
The main laboratory feature was moderate to severe granulocytopenia
(absolute neutrophil count: 0.23x109/l,
1.39x109/l and 0.81x109/l, respectively). All
patients had normal Hb level, RBC and platelet counts and none of
them exhibited any clinical and laboratory signs of hemolysis
(reticulocyte count, serum bilirubin, LDH and haptoglobin were
within normal limits). Flow cytometric analysis of peripheral blood
revealed a significant number of GPI-AP-deficient granulocytes in
all patients, but no CD59 or CD55 deficient RBC except for a small
PNH RBC clone in patient Nr.3. In patient Nr.1 (50 years old male)
who exhibited 30-35% of GPI-AP-deficient granulocytes, sequencing
analysis of PIG-A gene discovered transition C/T in exon 3, causing
a missense substitution at codon 248 (P248L). Patient Nr.2 was a 28
years female with 20% of GPI-AP-deficient granulocytes, with
sequentially identified transition G/A in exon 6 of PIG-A gene
resulting in replacement of glutamic acid by lysine at codon 482
(E482K). In patient Nr.3 (34 years old male), flow cytometric
analysis revealed 40-45% of PNH granulocytes and 8-12% of CD59 and
CD55 deficient RBC. In this patient, sequencing analysis of PIG-A
gene revealed transversion A/T in exon 5, leading to a non-sense
mutation at codon 367, forming a preterminal STOP codon. This
mutation resulted in the loss of 117 aminoacids from the C-terminus
of the protein. Our results suggest that unexplained profound
granulocytopenia may be in some patients related to mutation of
PIG-A gene leading to GPI-APs deficiency expressed predominantly on
granulocytes. MDS patients with isolated granulocytopenia who are
mostly diagnosed as unclassifiable RA according to the WHO criteria
should be screened by sensitive flow cytometry methods for presence
of GPI-APs deficient granulocytes. Evidence of a PNH clone may have
a prognostic value and may be helpful for decision of an optimal
treatment strategy, including immunosuppression.
Datum přednesení příspěvku: 10. 12. 2006