Clonal stability in children with acute lymphoblastic leukemia (ALL) who relapsed five or more years after diagnosis

Abstract

Although most relapses of childhood acute lymphoblastic leukemia (ALL) occur 24-36 months after first CR has been achieved, few patients relapse 5 or more years after CR achievement. The assessment of clonality has proved to be useful in determining whether even those very late events represent the reoccurrence of the original clone or alternatively a secondary leukemia. To gain further information on clonal stability in such late relapse, we performed detailed comparative Southern blotting and PCR analyses of TcR␦ and TcR␥ gene rearrangements in five ALL at presentation and subsequent relapse which occurred more than 5 years after diagnosis. At least one stable rearranged allele of the TcR␦ and TcR␥ loci was traced in all cases at presentation and clinical relapse despite a wide heterogeneity of the pattern of rearrangements. Our study extends to a larger series of patients previous findings which have sought to analyze the phenomenon of clonal evolution in children relapsed after more than 5 years of CCR. With respect to the potential pitfalls in monitoring minimal residual disease in childhood ALL for the presence of clonal evolution, our results highlight the combination of two target genes (such as TcR␥ and TcR␦) as a tool to reduce false negative MRD results.

Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL

“…50 Such clonal evolution at relapse has indeed been described in two patients, associated in one case with a phenotypic shift from CD3 À T-ALL to TCRab þ T-ALL. 21,22 Nevertheless, in concordance with our study, the vast majority of previously described T-ALL patients analyzed at diagnosis and relapse showed a fully stable TCRD configuration. 19,21,22 In contrast to TCRD gene rearrangements, which are detectable in only half of the T-ALL patients, TCRG gene rearrangements are present in approximately 95% of T-ALL patients 31 and accordingly could be identified in 34 out of 35 patients in our study.…”

“…21,22 Nevertheless, in concordance with our study, the vast majority of previously described T-ALL patients analyzed at diagnosis and relapse showed a fully stable TCRD configuration. 19,21,22 In contrast to TCRD gene rearrangements, which are detectable in only half of the T-ALL patients, TCRG gene rearrangements are present in approximately 95% of T-ALL patients 31 and accordingly could be identified in 34 out of 35 patients in our study. In 85% (29 of 34) of patients, the TCRG gene configuration was fully identical between diagnosis and relapse, and in 91% (31 of 34) of patients at least one TCRG rearrangement was preserved.…”

“…[19][20][21][22] Therefore, we studied the stability of the TCR gene rearrangements currently used for MRD monitoring in T-ALL, that is, TCR beta (TCRB), TCRG, TCRD, and TAL1 gene rearrangements in a series of 37 relapsed T-ALL patients (28 children and nine adults). This information formed the basis for reliable selection of MRD-PCR targets in T-ALL patients with minimal chance of false-negative MRD results.…”

Clonality profile in relapsed precursor-B-ALL children by GeneScan and sequencing analyses. Consequences on minimal residual disease monitoring

“…1,2,33 The investigation of clonality profiles by means of Ig/TCR gene rearrangements is a very powerful tool for understanding whether relapse represents the reoccurrence of the original leukaemic clone/s or a secondary malignancy. 17,[34][35][36][37][38][39][40][41][42] The existence of at least one conserved rearranged clonal target confirms that relapse is probably related to the diagnostic clone.…”

Immunoglobulin light chain gene rearrangements display hierarchy in absence of selection for functionality in precursor-B-ALL

“…8,9 Such prolonged recombinase activity might also affect clonal evolution after diagnosis, resulting in differences in rearrangement patterns between diagnosis and relapse. [18][19][20] However, a more likely explanation for the differences observed between genotypes in normal vs malignant precursor-B cells, is the lack of proper selection for functionality of the rearrangements due to the malignant status of the cell. We therefore believe that precursor-B-ALL rather con-…”