Figure 1
Figure 1. Patterns of evolution of FL and t-FL. (A,B) Two examples of genealogic trees generated by comparison of cloned IgH-VH PCR products and by heteroduplex (HH) analysis, from FL and t-FL samples. The putative CPC sequences were generated by comparison of the common pattern of SHMs observed in the paired FL and t-FL samples. The FL sequences are depicted as , the t-FL clones as ○, and the germline sequence as ·. The putative common progenitor cell and the hypothetical intermediate sequences, which were not detected experimentally, are depicted as . HH corresponds to the sequence identified by HH analysis. Numbers inside the circles correspond to the number of clones with the same sequence, and the numbers beside the arrows represent the additional mutations in the subsequent clone. The roman numbers I, II, III, and so on, on the trees, refer to the intermediate clones. (A) Genealogic trees of patient 1, a case compatible with the existence of a CPC. Genealogic trees generated after comparison of sequences obtained after screening of the FL and t-FL cloned PCR products (i-iii) and after comparison of the homoduplex sequences (iv); (v) graphic timeline representation of the FL/t-FL biopsies investigated and of clinical evolution of disease: vertical arrow represents the line of therapy (either chemotherapy or radiotherapy); left-hand vertical bar, the time of diagnosis; the right-hand vertical bar, time of death; R1, the first relapse; Tr1, the first transformation. (B) Genealogic trees of patient 2, a case compatible with a direct evolution. In this case an additional FL sample (FL2) was investigated. Genealogic tree generated after comparison of the cloned sequences (vi) and of the 2 major clones identified by HH analysis (vii); graphic timeline representation of the sequential biopsies investigated and the clinical evolution of disease: each vertical arrow represents a line of therapy; the bar at the end of the horizontal line, time the death; ww, watch and wait; P, progression; Tr1, first transformation; and R1, first relapse. (C) Models for development and evolution of the CPC cell. The CPC, FL, and t-FL clones are depicted as previously described. Letters a, b, and c represent the 3 patterns of evolution. Pre-B cells acquire the t(14;18) translocation in the bone marrow and then migrate to the GC of the lymph node as a naive B cell. There, because of the interaction with cells of the microenvironment, they undergo the SHM process to give rise to mature B cells. The first hypothesis (i) is that CPC survives the different lines of therapy and coexist with FL and t-FL clones in the GC. The second hypothesis (ii) suggests that the CPC is present only in the GC of the prelymphoma (normal follicle) lymph node and not in the GC of FL or t-FL. The third hypothesis (iii) is that the CPC migrates to the BM (before or after FL) and is maintained in the BM niche before migrating to a secondary lymphoid organ where it evolves into FL or t-FL. The second (ii) and third (iii) evolution pathways both relate to the existence of “premalignant” niches (the first one in the GC and the second one in the BM) where CPC can independently give rise to FL or t-FL.

Patterns of evolution of FL and t-FL. (A,B) Two examples of genealogic trees generated by comparison of cloned IgH-VH PCR products and by heteroduplex (HH) analysis, from FL and t-FL samples. The putative CPC sequences were generated by comparison of the common pattern of SHMs observed in the paired FL and t-FL samples. The FL sequences are depicted as , the t-FL clones as ○, and the germline sequence as ·. The putative common progenitor cell and the hypothetical intermediate sequences, which were not detected experimentally, are depicted as . HH corresponds to the sequence identified by HH analysis. Numbers inside the circles correspond to the number of clones with the same sequence, and the numbers beside the arrows represent the additional mutations in the subsequent clone. The roman numbers I, II, III, and so on, on the trees, refer to the intermediate clones. (A) Genealogic trees of patient 1, a case compatible with the existence of a CPC. Genealogic trees generated after comparison of sequences obtained after screening of the FL and t-FL cloned PCR products (i-iii) and after comparison of the homoduplex sequences (iv); (v) graphic timeline representation of the FL/t-FL biopsies investigated and of clinical evolution of disease: vertical arrow represents the line of therapy (either chemotherapy or radiotherapy); left-hand vertical bar, the time of diagnosis; the right-hand vertical bar, time of death; R1, the first relapse; Tr1, the first transformation. (B) Genealogic trees of patient 2, a case compatible with a direct evolution. In this case an additional FL sample (FL2) was investigated. Genealogic tree generated after comparison of the cloned sequences (vi) and of the 2 major clones identified by HH analysis (vii); graphic timeline representation of the sequential biopsies investigated and the clinical evolution of disease: each vertical arrow represents a line of therapy; the bar at the end of the horizontal line, time the death; ww, watch and wait; P, progression; Tr1, first transformation; and R1, first relapse. (C) Models for development and evolution of the CPC cell. The CPC, FL, and t-FL clones are depicted as previously described. Letters a, b, and c represent the 3 patterns of evolution. Pre-B cells acquire the t(14;18) translocation in the bone marrow and then migrate to the GC of the lymph node as a naive B cell. There, because of the interaction with cells of the microenvironment, they undergo the SHM process to give rise to mature B cells. The first hypothesis (i) is that CPC survives the different lines of therapy and coexist with FL and t-FL clones in the GC. The second hypothesis (ii) suggests that the CPC is present only in the GC of the prelymphoma (normal follicle) lymph node and not in the GC of FL or t-FL. The third hypothesis (iii) is that the CPC migrates to the BM (before or after FL) and is maintained in the BM niche before migrating to a secondary lymphoid organ where it evolves into FL or t-FL. The second (ii) and third (iii) evolution pathways both relate to the existence of “premalignant” niches (the first one in the GC and the second one in the BM) where CPC can independently give rise to FL or t-FL.

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