Evolution of Tumor Clones in Adult Acute Lymphoblastic Leukemia

Abstract

Clonal instability of a tumor cell population in acute lymphoblastic leukemia (ALL) may complicate the monitoring of a minimal residual disease (MRD) by means of patient-specific targets identified at the disease onset. Most of the data concerning the possible instability of rearranged clonal TCR and IG genes during disease recurrence were obtained for ALL in children. The appropriate features of adult ALL, which are known to differ from those of childhood ALL in certain biological characteristics and prognosis, remain insufficiently studied. The aim of this study was to assess the stability of IG and TCR gene rearrangements in adult ALL. Rearrangements were identified according to the BIOMED-2 protocol (PCR followed by fragment analysis). Mismatch in clonal rearrangements at onset and relapse was identified in 83% of patients, indicating clonal instability during treatment. Clonal evolution and diversity of IG and TCR gene rearrangements may be one of the tumor progression mechanisms. New rearrangements may emerge due to residual VDJ-recombinase activity in tumor cells. Also, many clonal IG and TCR gene rearrangements may be present at different levels at a diagnosis, but less abundant clones may be "invisible" due to limited detection sensitivity. Later, major clones may disappear in the course of chemotherapy, while others may proliferate. Investigation of clonal evolution and heterogeneity in ALL and their impact on the treatment efficacy will contribute to the identification of new prognostic factors and the development of therapeutic approaches.

Keywords: IG and TCR gene rearrangements; acute lymphoblastic leukemia; relapse.

Fig. 1

Fragment analysis of TCR, TCD, and IGH gene amplification products in patient 5 at the onset and relapse. Two 142 and 207 bp clonal products (indicated by arrows) of TCRD gene rearrangements and a 347 bp clonal product of IGH gene rearrangements were amplified at the disease onset. In this patient, the rearrangements remained at the relapse and new clonal products were also identified (TCRGA – 164 bp, TCRGB – 151 and 165 bp; IGHA – 330 bp, IGHB – 263 bp, IGHC – 127 bp).

Fig. 2

Fragment analysis of TCRG, TCRD, IGK, and TCRB gene amplification products in patient 4 at the onset and relapse. Seven clonal rearrangements were identified at the diagnosis. Only two of them were preserved at the relapse (TCRD – 124 bp; IGK – 283 bp).