Chronic myeloid leukemia stem cells in the era of targeted therapies: resistance, persistence and long-term dormancy

Abstract

Targeted therapies of chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKI) have profoundly changed the natural history of the disease with a major impact on survival. Molecular monitoring with BCR-ABL quantification shows that a status of undetectable molecular residual disease (UMRD) is obtained in a significant minority of patients. However, it remains unclear whether these patients are definitively cured of their leukemia. Imatinib mesylate withdrawal trials have demonstrated the rapid appearance of the malignant clone in the majority of the patients whereas some patients remain in a state of UMRD. It has clearly been demonstrated that the most primitive stem cells are refractory to all TKIs used in clinical practice. In addition, long-term dormancy is one of the most fundamental characteristics of hematopoietic stem cells. In this context, we have recently undertaken a systematic analysis of the bone marrow stem cell compartment in several patients in durable UMRD. We have demonstrated the long-term persistence of a considerable amount of BCR-ABL-expressing stem cells, even in the absence of relapse. The phenomenon of long-term leukemic stem cell dormancy is of major importance in CML and one of the key questions in cancer biology in general. We discuss, here, the potential mechanisms, including intrinsic and microenvironmental factors, that control the response of leukemic stem cells (LSCs) to targeted therapies and potential novel strategies currently in progress with a curative intent. Moreover, we propose a molecular evaluation of the residual LSC compartment in selected patients in order to develop rational TKI-cessation strategies in CML.

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

“…Despite advances in melanoma research and drug development, 10-20% of clinically disease-free patients relapse 5-10 years following an initial treatment [1,2]. This phenomenon, which is known as tumor dormancy [3], has been related to the existence of therapy-resistant cells with stem-like activity [4][5][6]. Recent findings suggest that cancer stem cells, in response to chemotherapy, enter protective, prolonged, but reversible, quiescence [7] and remain dormant without causing any clinical manifestations until activated [8].…”

ABCB1regulation through LRPPRC is influenced by the methylation status of the GC -100 box in its promoter

“…It is still unclear how typical MDR (ABC transporters) and atypical MDR (non ABC transporters) are regulated and how they fit into the new molecular target therapy. [46][47][48] Our previous work demonstrated that LRPPRC was potentially involved in IM and MDR cross-resistance. LRPPRC is a 130 kDa protein that was first described in hepatocarcinoma cells.…”

Optimal control analysis of a leukemia model under imatinib treatment

“…The controls u, u 1 and u 2 stand for the drug effects on CML cells. Since the exact effect of Imatinib on the leukemic cells is still under debate (see the review by Chomel et al 2011 [10]), it is important to explore all possibilities. However, it is known that, because Imatinib is a tyrosine kinase inhibitor, it does not directly kill the leukemic cells, but slows down their proliferation and stabilizes all other abnormal processes that provide cancerous cells a proliferative advantage.…”