Chronic myeloid leukemia: mechanisms of blastic transformation
Danilo Perrotti, Catriona Jamieson, John Goldman, Tomasz Skorski
Danilo Perrotti, Catriona Jamieson, John Goldman, Tomasz Skorski
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Science in Medicine

Chronic myeloid leukemia: mechanisms of blastic transformation

Abstract

The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.

Authors

Danilo Perrotti, Catriona Jamieson, John Goldman, Tomasz Skorski

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Figure 2

BCR-ABL1 and PP2A interplay.

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BCR-ABL1 and PP2A interplay. (A) In CML-BP and Ph-positive ALL CD34+ pro...
(A) In CML-BP and Ph-positive ALL CD34+ progenitors, p210 and p190 BCR-ABL1 oncoproteins inhibit PP2A activity by inducing hnRNP-A1, which, in turn, enhances expression of SET. In BCR-ABL–positive myeloid progenitor cells, suppression of PP2A phosphatase activity is required for sustained activation of mitogenic and survival signals. (B) Restored PP2A activity, achieved by treatment with PP2A activators (e.g., Forskolin or FTY720), impairs in vitro and in vivo wild-type and T315I BCR-ABL1 leukemogenesis by antagonizing the effects of BCR-ABL1 on its downstream signal transducers (not shown) and promoting SHP-1–mediated BCR-ABL1 inactivation and proteasome-dependent degradation.