Do we have to kill the last CML cell?

Ross, David M.; Hughes, Timothy P.; Melo, Junia V.

doi:10.1038/leu.2010.197

Cited by 35 publications

(20 citation statements)

References 88 publications

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“…In fact, the presence of the TK BCR-ABL as the sole cause of CML development has provided the challenge of finding the perfect drug able to specifically inhibit the oncogene. Although considerable advances in the treatment of CML have been made with the development of the TKIs IM, dasatinib, and nilotinib, primitive CML stem cells remain insensitive to these compounds, and no test is yet available to definitely show that CML stem cells have been eradicated [5,13,[50][51][52].…”

Section: Discussionmentioning

confidence: 99%

In Search of CML Stem Cells’ Deadly Weakness

Pellicano

Sinclair

Holyoake

2011

Curr Hematol Malig Rep

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a fusion oncogene, BCR-ABL, which encodes a protein with constitutive tyrosine kinase activity. This activity causes excessive production of myeloid cells and their premature release into the circulation. The discovery of tyrosine kinase inhibitors marked a major advance in CML therapy, but these drugs cannot eradicate the disease because they are unable to kill the most primitive, quiescent leukemic stem cells. This review discusses current research in CML and attractive targets that have emerged with potential for eradicating the disease. Several new targets have recently been investigated as potential modulators in myeloid leukemia pathogenesis, including the multiple gene regulators miRNAs, the apparently leukemia-specific cell surface marker IL1RAP, transcription factors such as BMI1 and FOXOs, the tumor suppressors PML and PP2A, and the tyrosine kinase JAK2.

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Section: Discussionmentioning

confidence: 99%

In Search of CML Stem Cells’ Deadly Weakness

Pellicano

Sinclair

Holyoake

2011

Curr Hematol Malig Rep

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“…19 For months or years after achieving a complete cytogenetic response, most patients with CML treated with imatinib mesylate have measurable disease by RQ-PCR and would relapse if imatinib mesylate therapy were discontinued. 20,21 However, in most patients who respond to imatinib mesylate, there is a progressive decline in the BCR-ABL1 counts over time, such that after several years of treatment an increasing number of patients achieve a complete molecular response within the limitations of the assay.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells

Tang

Gönen

Quintás‐Cardama

et al. 2011

Blood

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Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of -0.052 ± 0.018 (imatinib mesylate) and -0.042 ± 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of -0.0057 ± 0.0038 (imatinib mesylate) and -0.0019 ± 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients.

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“…Conversely, some studies hypothesize that long-term TKI therapy (especially with the 2 nd generation drugs) could significantly reduce the malignant stem cell compartment. It has also been reported that it was not necessary to kill the last leukemic cell [118]. Nevertheless, TKI therapy alone seems unlikely to be fully curative, and a risk of relapse subsists even in sustained UMRD.…”

Section: Discussionmentioning

confidence: 99%

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

Chomel¹,

Turhan²

2011

Oncotarget

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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.

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Do we have to kill the last CML cell?

Cited by 35 publications

References 88 publications

In Search of CML Stem Cells’ Deadly Weakness

In Search of CML Stem Cells’ Deadly Weakness

Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells

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

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