Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia.
In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts at diagnosis day 0 (d0) and persisting on day 8 (d8). Expression changes indicate a shift towards mature B cells, inhibition of cell cycling and increased expression of adhesion (CD11b/ITGAM) and cytokine (CD119/IFNGR1) receptors. A direct comparison with normal B cells, which are largely therapy resistant, confirmed the differentiation shift at the mRNA (n=10) and protein (n=109) levels. Flow cytometric analysis in independent cohorts of patients confirmed both a decreased proliferative activity (n=13) and the upregulation of CD11b and CD119 (n=29) in d8 blasts. The differentiation shift and low proliferative activity in d8 blasts may account for the persistence of blasts during therapy and affect their sensitivity to further therapeutic treatment. CD11b and CD119 are potential specific markers for d8 blast persistence and detection of minimal residual disease, which warrant further investigation.
Rhein
P
P
Department of Hematology, Oncology, and Tumor Immunology, Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin, Germany.
Scheid
S
S
Ratei
R
R
Hagemeier
C
C
Seeger
K
K
Kirschner-Schwabe
R
R
Moericke
A
A
Schrappe
M
M
Spang
R
R
Ludwig
W-D
WD
Karawajew
L
L
D000293:Adolescent; D001402:B-Lymphocytes / Q000378:metabolism*; D001752:Blast Crisis / Q000378:metabolism*; D039481:CD11b Antigen / Q000032:analysis; D002453:Cell Cycle; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011241:Prednisone / Q000627:therapeutic use; D017471:Receptors, Interferon / Q000032:analysis; D000096743:Interferon gamma Receptor
D039481:CD11b Antigen; D008727:Methotrexate; D011241:Prednisone; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor