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Cell and molecular biology of human leukaemias 

Cell and molecular biology of human leukaemias

Cell and molecular biology of human leukaemias

Alejandro Gutierrez

and A. Thomas Look

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date: 24 April 2017

The human leukaemias arise when haematopoietic stem and progenitor cells acquire genetic alterations that lead to malignant transformation, following which affected cells can exhibit differentiation arrest in any lineage and at any stage of maturation.

Genetic alterations leading to leukaemia—a recurring theme is that the genes most frequently altered are those with evolutionarily conserved roles in the embryological development of various cell lineages and organ systems, including (but not limited to) genes that control normal haematopoiesis. The molecular genetic alterations that drive leukaemogenesis can generally be characterized into lesions affecting transcription factors and those that aberrantly activate signal transduction pathways, which often occur via activating mutations in tyrosine kinases.

The effects of leukaemogenic genetic alterations—some of these affect cell proliferation or survival, whereas others exert their primary effects on cell differentiation. The critical lesion almost always involves a ‘master’ transcriptional regulatory gene or tyrosine kinase signalling molecule that stands near the top of a hierarchy of gene control, such that leukaemia is efficiently instigated by a limited number of alterations rather than by multiple changes affecting tens of responder genes in the biochemical cascade.

Cell and molecular biology of particular leukaemias—(1) Acute lymphoblastic leukaemia and acute promyelocytic leukaemia—in most cases the initial lesion appears to affect progenitors at the same stage of differentiation as the predominant phenotype in the malignant clone. (2) Acute myeloid leukaemia and chronic myeloid leukaemia—most cases appear to arise in a primitive haemopoietic stem cell rather than a committed myeloid progenitor, with subsequent blockade of differentiation at a later developmental stage that determines the morphological subtypes of myeloid leukaemia apparent at diagnosis; this may also be the situation in some cases of acute lymphoblastic leukaemia, at least those expressing the BCR-ABL1 fusion oncogene. (3) Chronic lymphocytic leukaemia—it is currently believed that defective apoptosis in vivo is the primary pathogenic abnormality.

Acknowledgements: The authors would like to thank John Gilbert for editorial review and critical comments. Supported in part by NIH grant CA068484-12.

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