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Editorial
. 2013 Sep;98(9):1331-3.
doi: 10.3324/haematol.2013.091546.

Origin and migration of follicular lymphoma cells

Philip M Kluin
Editorial

Origin and migration of follicular lymphoma cells

Philip M Kluin. Haematologica. 2013 Sep.
No abstract available

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Figures

Figure 1.
Figure 1.
Models to explain the pattern of somatic hypermutations of the IGH locus in follicular lymphoma. Dotted arrows: premalignant t(14;18)-carrying B cells circulating in the body, as pre-germinal center B cells without accumulation of somatic hypermutation (red dotted arrow) but mainly as post-germinal center memory B cells (black dotted arrows). Straight black arrows: malignant t(14;18) carrying B cells circulating in the body, as post-germinal center memory B cells. The thickness of the lines indicates the load of somatic hypermutation in the B cells. Gray lymph nodes: normal lymph nodes that nevertheless may host t(14;18) positive “follicular lymphoma-like cells” (FLLC) as passengers, allowing them to expand and accumulate somatic mutations. Gray lymph nodes with single blue germinal center: idem, but containing FLIS. Blue lymph nodes: lymph nodes with follicular lymphoma. Green lymph nodes: lymph nodes with follicular lymphoma at relapse. (A) Model showing the original concept that the t(14;18) arises as an error in the bone marrow. Subsequently this cell is expanded in germinal centers of lymph nodes and other lymphoid organs, giving rise to follicular lymphoma after acquisition of additional genetic hits. (B) Model to explain the observed heterogeneity in mutational load in FL. This model suggests a stepwise accumulation of mutations with time, dependent on the frequency of re-entry in germinal centers and, thus the exposure to activation-induced deaminase (AID). (C) In this model new observations on premalignant FLLC that circulate in many healthy individuals but represent post-germinal center memory B cells are incorporated. Theoretically, some of these cells may colonize individual germinal centers and give rise to a “so-called follicular lymphoma in situ” (FLIS). Like malignant FL cells, these cells have already accumulated somatic mutations. Likely, in few individuals FLLC acquire additional oncogenic hits such as CREBBP mutations giving rise to a follicular lymphoma. (D) This model incorporates the observations published by Wartenberg et al. These authors suggest that relatively fewer mutated FL cells may find a niche in the bone marrow. These cells may be relatively quiescent and in consequence escape the effect of chemotherapy, and may repopulate the body after therapy (“founder cells”). This might explain why there is no linear accumulative load of somatic mutations in FL patients. In fact in some patients, biopsies at relapse show fewer mutations than in the original diagnostic biopsy. (E) Model similar to that shown in (D). However, this model shows the theoretical possibility that also premalignant FLLC migrate back to the bone marrow and colonize the bone marrow niches, giving rise to late relapses.
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References

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