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    • br Discussion Immunodeficiency may facilitate the neoplastic

    2019-04-29


    Discussion Immunodeficiency may facilitate the neoplastic transformation of a premalignant clone. Primary immunodeficiency is well documented in patients with ataxia-telangiectasia (AT) and Bloom׳s Syndrome (BS) and such immune deficient states are known to permit clonal expansion of glut1 with underlying mutations in the lymphoid and myeloid systems respectively [2]. The primary immunodeficiency as a contributory factor in the development of donor leukemia in the patient is unlikely. Secondary immunodeficiency due to chemotherapy and radiation administered is likely a possibility in leukemia arising following autologous stem cell transplantation with short latency period, but highly unlikely in this case given the long latency period of fourteen years in this case. We suggest, alternatively, that premature senescence and or programmed cell death of the normal transplanted donor stem cells due to telomere erosion may have played a role (Fig. 2). The difference in telomere dynamics between normal donor cells and donor cells with trisomy 11 may contribute significantly to the selective proliferation and neoplastic transformation of the latter. In fact, Notaro et al. (1997)[3] previously found that telomere length of engrafted donor cells was significantly reduced when compared to donor cells, suggesting that telomere shortening may reduce the proliferative potential of the engrafted donor cells. In addition, it is also well recognized that telomere erosion also results in a significant genomic instability, the hall mark of malignant transformation [4]. It is furthermore known that following allogeneic stem cell transplantation, the reduction in telomere length of donor hematopoietic cells is equivalent to approximately 15 years, and in some instances 40–60 years, of aging [5,6]. Several studies suggest that the reduction in telomere length, which occurs predominantly during the first year following transplantation, is unlikely to significantly compromise bone marrow function. However, it is important to recognize that such data is largely derived from a younger donor and recipient population (age<40) [7]. It is therefore conceivable that in the present case, with an older donor (54 at the time of stem collection), this well recognized reduction in telomere length may have compounded the overall effect of this phenomenon. Therefore, normal stem cells from an older donor are placed under replicative stress, which in turn may reduce the proliferative capacity of these cells [3]. The resulting senescence of normal donor hematopoietic cells over the 14 years following transplantation in our patient may have set the stage for the expansion of cells with trisomy 11. The amplification of MLL protein in these, now dividing cells may have triggered a cascade of events leading to frank leukemia [8]. Several studies reviewed elsewhere have suggested that amplification of MLL gene may activate HOX genes which are known to play important role in leukemogenesis [8]. Lastly, it is equally important to mention that the microenvironment and genetic background of the host with a previous history of two independent malignancies may have further facilitated the selective proliferation of a clone with trisomy 11 [9,10], while normal cells suffered proliferative stress resulting in senescence or apoptosis. We, therefore, propose that the sequence of genetic and epigenetic events leading to leukemogenesis of donor cells with trisomy 11 includes telomere shortening in normal donor derived hematopoietic stem cells due to excessive stress to reconstitute host hematopoietic compartment, results in selective proliferation of a clone with MLL amplification, which in turn activated genes such as HOX, known to be deregulated in MDS and AML [8].
    Authorship
    Introduction Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, hyperinflammatory syndrome that is often fatal when treatment is delayed [1]. Diagnosis may be difficult due to the wide range of symptoms associated with HLH and lack of specific diagnostic tests. Genetic causes of familial HLH relate to defects in cytotoxic granule exocytosis or function, whereas the acquired or secondary form is often associated with infection, malignancy, or autoimmune/immunodeficiency conditions. Defects in cytotoxic T cells and natural killer (NK) cells are seen in nearly all cases of HLH [1]. Hematologic neoplasms account for the majority of malignancy-associated HLH, and T-cell malignancies predominate. HLH associated with underlying B-cell lymphoma is rare, and seems to occur in older patients with a low incidence of marrow involvement by lymphoma [2]. Here, we describe a case of HLH arising in a young patient with diffuse marrow involvement by T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), a subtype representing 1–3% of diffuse large B-cell lymphomas (DLBCL) with a characteristic background of cytotoxic T cells and histiocytes.
    Clinical presentation