The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells.
The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre-B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells. Although normal pre-B cells are selected for the expression of a functional pre-B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre-B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre-B cell receptor signaling and the expression of a truncated isoform of the pre-B cell receptor-associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre-) B cell receptor.
Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-Universität Düsseldorf, 40225, Germany.
Florian
F
Klein
Niklas
N
Feldhahn
Lana
L
Harder
Hui
H
Wang
Maria
M
Wartenberg
Wolf-Karsten
WK
Hofmann
Peter
P
Wernet
Reiner
R
Siebert
Markus
M
Müschen
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl; D015870:Gene Expression; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D054420:Pre-B Cell Receptors; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011947:Receptors, Antigen, B-Cell; D012641:Selection, Genetic
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D054420:Pre-B Cell Receptors; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl