Prognostic impact of genetic instability in CD34 positive hemat opoietic progenitor cells from patients with AML in first complete remission

Abstract

Autologous transplantation in de novo AML may provide us with some
clues to the nature of leukemogenesis. The present study used for the first
time positively selected CD34+ cells from leukapheresis products (<0.1%
minimal residual disease by FACS analysis) collected during first complete
remission (CR) of de novo AML (n = 43) following double induction
or consolidation according AMLCG protocol, to study the genetic instability
(GIN defined as microsatellite instability (MSI), >2 loss of heterozygosity
(LOH) or MSI or LOH at APC locus) in the remission
hematopoiesis and the corresponding CD34- fractions, mainly lymphocytes.
Altogether 40 events at 8 of 10 tested loci were identified in CD34+
cells of 22 patients (51%), MSI (n = 20), LOH (n = 30). LOH and MSI
was observed on the following chromosome arms: 2p (n = 2, hMSH2), 5q
(n = 9, APC), 7q (n = 5, D5486, c-met), 8q (n = 8, Eto), 11q (n = 6, MLL),
17q (n = 9, BRCA1, TP53). No genetic instability was detected in CD34+
cells of 5 healthy subjects. None of the clinical parameters at diagnosis
(LDH, cytogenetics, blast counts in bone marrow) were correlated with
GIN. In multivariate analysis GIN was an independent prognostic factor
for relapse-free survival (p = 0.008). In conclusion hematopoiesis in patients
with AML in first CR suffers frequently from genetic changes
below the cytogenetic level. Prospective studies on GIN are required to
evaluate the therapeutic implications.