HETEROGENEITY IN JUNCTIONAL REGIONS OF IMMUNOGLOBULIN-KAPPA DELETING ELEMENT REARRANGEMENTS IN B-CELL LEUKEMIAS - A NEW MOLECULAR TARGET FOR DETECTION OF MINIMAL RESIDUAL DISEASE
A. Beishuizen et al., HETEROGENEITY IN JUNCTIONAL REGIONS OF IMMUNOGLOBULIN-KAPPA DELETING ELEMENT REARRANGEMENTS IN B-CELL LEUKEMIAS - A NEW MOLECULAR TARGET FOR DETECTION OF MINIMAL RESIDUAL DISEASE, Leukemia, 11(12), 1997, pp. 2200-2207
Virtually all immunoglobulin kappa (IGK) gene deletions are mediated v
ia rearrangements of the so-called kappa deleting element (Kde), Kde r
earrangements occur either to V kappa gene segments (V kappa-Kde rearr
angements) of to the heptamer recombination signal sequence in the J k
appa-C kappa. intron. Kde rearrangements were analyzed by the polymera
se chain reaction (PCR) and heteroduplex analysis in 130 B-lineage leu
kemias: 63 precursor-B-acute lymphoblastic leukemias (ALL) and 67 chro
nic B cell leukemias, To obtain detailed information about Kde rearran
gements, we sequenced 109 of the 189 detected junctional regions. V ka
ppa gene family usage in the V kappa-Kde rearrangements in our series
of B-lineage leukemias was comparable to V kappa gene family usage in
functional V kappa-J kappa rearrangements in normal and malignant matu
re B cells, except far a higher frequency of V kappa II family usage i
n precursor-B-ALL, Junctional region sequencing of the Kde rearrangeme
nts in precursor-B-ALL revealed a mean insertion of 4.7 nucleotides an
d a mean deletion of 9.5 nucleotides, resulting in an extensive juncti
onal diversity, whereas in chronic B cell leukemias the insertion (1.9
) and deletion (6.0) were significantly lower, The relatively extensiv
e junctional diversity of the Kde rearrangements in precursor-B-ALL al
lowed us to design leukemia/patient-specific oligonucleotide probes, w
hich were proven to be useful for detection of minimal residual diseas
e (MRD) with sensitivities of 10(-4) to 10(-5) Kde rearrangements occu
r in approximately 50% of precursor-B-ALL cases and are likely to rema
in stable during the disease course, because Kde rearrangements are as
sumed to be 'end-stage' rearrangements, which cannot easily be replace
d by continuing rearrangement processes. These findings indicate that
junctional regions of Kde rearrangements in precursor-B-ALL represent
new valuable patient-specific PCR targets for detection of MRD.