title: A multicellular basis for the origination of blast crisis in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is characterized by a specific chromosome translocation, and its pathobiology is considered comparatively well understood. Thus, quantitative analysis of CML and its progression to blast crisis may help elucidate general mechanisms of carcinogenesis and cancer progression. Hitherto, it has been widely postulated that CML blast crisis originates mainly via cell-autonomous mechanisms such as secondary mutations or genomic instability. However, recent results suggest that carcinogenic transformation may be an inherently multicellular event, in departure from the classic unicellular paradigm. We investigate this possibility in the case of blast crisis origination in CML. A quantitative, mechanistic cell population dynamics model was employed. This model used recent data on imatinib-treated CML; it also used earlier clinical data, not previously incorporated into current mathematical CML/imatinib models. With the pre-imatinib data, which include results on many more blast crises, we obtained evidence that the driving mechanism for blast crisis origination is a cooperation between specific cell types. Assuming leukemic-normal interactions resulted in a statistically significant improvement over assuming either cell-autonomous mechanisms or interactions between leukemic cells. This conclusion was robust with regard to changes in the model's adjustable parameters. Application of the results to patients treated with imatinib suggests that imatinib may act not only on malignant blast precursors, but also, to a limited degree, on the malignant blasts themselves.
authors.affiliation: Department of Mathematics, University of California, Berkeley, California 94720, USA. sachs@math.berkeley.edu
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Sachs
authors.forename: Kerstin
authors.initials: K
authors.lastname: Johnsson
authors.forename: Philip
authors.initials: P
authors.lastname: Hahnfeldt
authors.forename: Janet
authors.initials: J
authors.lastname: Luo
authors.forename: Allen
authors.initials: A
authors.lastname: Chen
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
mesh_terms: D001752:Blast Crisis / Q000473:pathology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008954:Models, Biological