Expression of late cell cycle genes and an increased proliferative capacity characterize very early relapse of childhood acute lymphoblastic leukemia.
OBJECTIVE
In childhood acute lymphoblastic leukemia (ALL), approximately 25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood.


METHODS
Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group.


RESULTS
We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G(2)-M phase cells and this correlated well with the expression level of cell cycle genes.


CONCLUSIONS
Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.
Kirschner-Schwabe
Renate
R
Department of Pediatric Oncology/Hematology, HELIOS Klinikum Berlin, Robert-Roessle-Clinic, Laboratory for Functional Genomics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Lottaz
Claudio
C
Tödling
Jörn
J
Rhein
Peter
P
Karawajew
Leonid
L
Eckert
Cornelia
C
von Stackelberg
Arend
A
Ungethüm
Ute
U
Kostka
Dennis
D
Kulozik
Andreas E
AE
Ludwig
Wolf-Dieter
WD
Henze
Günter
G
Spang
Rainer
R
Hagemeier
Christian
C
Seeger
Karl
K
D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation / Q000235:genetics
D018797:Cell Cycle Proteins