A new era in blood and lymphatic cancer biology and therapy

Correspondence: David Dingli Mayo Clinic, Division of Hematology, 200 First Street SW, rochester, MN 55905, USA Tel +1 507 284 3178 Fax +1 507 266 2122 Email dingli.david@mayo.edu Tumors derived from the transformation of hematopoietic or lymphoid cells are increasing in incidence and with improvements in therapy, their prevalence is also growing. The increasing availability of more sophisticated molecular tools is refining the definition of these diseases and now more than ever, we are on the verge of ‘personalized medicine’. No disease is as personal as cancer. The current view of tumorigenesis is that somatic cells serially acquire mutations that lead to the malignant phenotype, a state characterized by loss of cell cycle regulation, resistance to apoptosis, unbridled cellular proliferation, angiogenesis, evasion of the immune response, and ultimately, invasion of other tissues. Although many somatic mutations probably do not provide a reproductive advantage to cells or can even be deleterious, some mutations enhance the reproductive fitness of the cell enabling it to expand into a clone where additional mutations may lead to the full malignant phenotype. Given that evolution is the result of reproduction, mutation and selection, cancer is a natural consequence, especially in large multicellular organisms that can live for many years. Exposure to genotoxic agents (chemicals, viruses, radiation) or the response to chronic injury increases the risk of transformation since at some level, the risk is related to the number of cells that are dividing and how often they divide. It is not yet clear how many mutations are required to lead to the cancer phenotype but perhaps with very few exceptions, one mutation is not enough to lead to neoplastic transformation and disease. In most tissues (including hematopoiesis) there is significant cell turnover but the majority of cells do not survive for long, and the amplifying population of cells is generally maintained by a small population of tissue-specific stem cells that in general replicate slowly. It is possible that evolution selected for this architecture to minimize the risk of acquisition and maintenance of mutant cells and therefore essentially limit the risk of cancer. One can consider all cells as continuously at risk of acquiring mutations that may bring them a step closer to the malignant phenotype. In essence, cells explore many genotype/phenotype possibilities in an aimless fashion, but if the environment provides an advantage for a clone this will expand and could lead to disease. This relatively simple view can explain the significant genetic heterogeneity that is being discovered in tumors that arise from the same tissue. Although some genetic defects may be shared, recent sequencing studies show that i) malignant cells harbor many mutated genes, ii) signaling pathways can exhibit significant cross talk and therefore be quite redundant, and iii) the spectrum of oncogenic mutations is much wider than oncogenes, tumor suppressor genes, B lo od a nd L ym ph at ic C an ce r: T ar ge ts a nd T he ra py d ow nl oa de d fr om h ttp s: //w w w .d ov ep re ss .c om / b y 54 .7 0. 40 .1 1 on 1 9D ec -2 01 8