Clonal evolution

NOWELL p c (1976) The clonal evolution of tumour cell populations . Science, 194, 23-8. 

The lymph node microenvironment represents a niche where CLL cells interact with different types of cells including monocyte-derived nurse-like cells (NLC), CD3+ CD4+ CD154+ T cells, mesenchymal stromal cells, dendritic cells, and endothelial cells (15). In addition to cell-cell interactions, CLL cells are also exposed to a variety of soluble factors such as antigens, cytokines, and chemokines (2). It is the combination of such signals that renders CLL cells less susceptible to chemotherapy and promotes clonal evolution and drug resistance. Thus, the role of the microenvironment needs to be carefully considered in order to develop novel and more effective therapies for CLL treatment (16). In particular, the efficacy of new drugs must be evaluated under experimental conditions that recapitulate (or at least partially mimic) the CLL microenvironment. 

Increased expression of BCR-ABL kinase from genomic amplification BCR-ABL independent mechanisms Clonal evolution (non- BCR-ABL-dependent mechanism) o Clonal evolution o Aneuploidy... 

Gene amplification of the BCR-ABL 1 kinase may be associated with development of IM resistance. The presence of multiple copies of the BCR-ABL 1 gene in interphase nuclei can be demonstrated by fluorescence in situ hybridization (FISH) (40,42). In one series, more than half of the patients with IM resistance had evidence of clonal evolution with the development of additional chromosome abnormalities. Paired cytogenetic analyses performed at the begiiming of IM therapy and at the time of resistance demonstrated this evolution. 

P. C. Nowell. The clonal evolution of tumor cell populations. Science.194, (4260), 23-28.1976. 

Clonal dominance has been reported to occur also in mammary tumors and metastases from human patients (Symmans et al., 1995), although a similar study performed on squamous cell carcinomas of the larynx found a more marked heterogeneity between primary tumors and their metastases (Sun et al., 1995), suggesting either subclone heterogeneity within the primary tumor at the time of establishment of metastasis, or further clonal evolution of both tumors and metastasis. 

Compared with untreated patients and patients treated with busulfan or hydroxyurea, interferon alfa produced a significantly higher frequency of clonal aberrant cytogenetic abnormalities and chronic clonal evolution in patients with chronic myeloid leukemia (386). However, the possible role of interferon alfa in the secondary occurrence of hematological malignancies is purely speculative. Only isolated cases of myeloproliferative syndrome, leukemia, or lymphoma have been attributed to interferon alfa (SED-13, 1098) (SEDA-20, 331) (SEDA-21, 373). There was no increased incidence of second cancers in patients treated for hairy cell leukemia (SEDA-20, 331). 

Asimakopoulos EA, Shteper PJ, Krichevsky S, et al. ABL methylation is a distinct molecular event associated with clonal evolution of chronic myelogenous leukemia. Blood 1999 94 2452-2460. 

As alluded to earlier, none of the antibodies considered in this section is effective at labeling more than a small fraction (<10%) of spindle-cell/desmoplas-tic/neuroid melanomas.This shortcoming is likely a reflection of the fact that such neoplasms typically manifest clonal evolution from a melanocytic phenotype to a more fibroblastic or schwannian motif, losing, in the process, their ability to synthesize premelanosomes and proteins related to those organelles. 

It is likely that MFH is not a unified entity in the skin or elsewhere, but instead represents a histologic pattern that is a common final pathway of differentiation for several modes of mesenchymal neoplasia. That concept was first espoused by Brooks. Thus an MFH-like pattern may be seen in conjunction with other mesenchymal images in the same tumor mass, as a consequence of clonal evolution. An unqualified diagnosis of MFH can be made immunohistologically only if one is dealing with a pleomorphic malignant tumor that is vimentin reactive and lacks epithelial, myogenous, neural, and endothelial markers. At present, there are no proactive determinants that define this neoplasm. 

Asimakopoulos, F.A., Shteper, P.J., Krichevsky, S., Fibach, E., PoUiack, A., Rachmilewitz, E., Ben-Neriah, Y., and Ben-Yehuda, D., ABLl methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia. Blood, 94 (7), 2452-2460, 1999. 

Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi OP, Isola J (1997) Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 57 1597-1604... 

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