Department of Mathematics, University of California, Berkeley, California 94720, USA.
Cancer Res. 2011 Apr 15;71(8):2838-47. doi: 10.1158/0008-5472.CAN-10-4600. Epub 2011 Apr 12.
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.
慢性髓细胞白血病（CML）的特征是一种特定的染色体易位，其病理生物学被认为相对容易理解。因此，对 CML 的定量分析及其向急变期的进展可能有助于阐明致癌和癌症进展的一般机制。迄今为止，人们广泛假设 CML 急变期主要通过细胞自主机制（如二次突变或基因组不稳定性）产生。然而，最近的结果表明，致癌转化可能是一种固有的多细胞事件，与经典的单细胞范式不同。我们在 CML 急变期起源的情况下研究了这种可能性。采用了一种定量的、基于机制的细胞群体动力学模型。该模型使用了最近关于伊马替尼治疗 CML 的数据；它还使用了早期的临床数据，这些数据以前没有纳入当前的数学 CML/伊马替尼模型。利用预伊马替尼数据，其中包括对更多急变期的结果，我们获得了证据，表明急变期起源的驱动机制是特定细胞类型之间的合作。与假设细胞自主机制或白血病细胞之间的相互作用相比，假设白血病-正常细胞相互作用导致了统计学上显著的改善。这一结论在模型可调参数发生变化时仍然是稳健的。将结果应用于接受伊马替尼治疗的患者表明，伊马替尼不仅可能作用于恶性原始细胞前体，而且在一定程度上也可能作用于恶性原始细胞本身。
