Maintaining Low BCR-ABL Signaling Output to Restrict CML Progression and Enable Persistence

Andreas Burchert

doi:10.1007/s11899-013-0196-8

Abstract

Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.

Highlights

Neoplastic transformation is considered to involve a sequence of independent mutations, which activateOn the other hand, tyrosine kinase inhibitors (TKI) therapy rarely leads to chronic myeloid leukemia (CML) stem cell eradication
TKI therapy rarely leads to CML stem cell eradication
Selection of persisting clones with low BCR-ABL signaling output has been suggested as an underlying mechanism of CML persistence by preventing BCR-ABL addiction and TKI sensitivity [16, 23]

Summary

Introduction

Neoplastic transformation is considered to involve a sequence of independent mutations, which activate. Tumors eventually become Myc-independent [43,44,45] This means, that an oncogene such as Myc (or BCR-ABL) can be instrumental for the initiation of tumorigenesis, secondary genetic or epigenetic changes may be required to tolerate elevated oncogenic stress and subsequently allow independence from the causative oncogene [46]. This has been demonstrated for the emergence of Kras mutations in Mycdependent mouse mammary tumors [44]. It is important to discuss, barriers against transformation in hematopoietic stem cells, when they are activated and how they fail

General Barriers Against Transformation

TKI treatment

Compliance with Ethics Guidelines

Findings

Potential Clinical Implications