Punish the parent not the progeny

Abstract

Chronic myeloid leukemia (CML) is sustained by a rare population of primitive, quiescent, BCR-ABL ؉ cells and represents an excellent example of a malignancy in which tumor-initiating cells represent the key to disease eradication. CML is also the first malignancy for which targeted therapy has replaced conventional chemotherapy. Within a vast excess of proliferating progenitor cells that express breakpoint cluster region-abelson (BCR-ABL) and are exquisitely sensitive to the tyrosine kinase inhibitor imatinib mesylate (IM) resides a small population of quiescent leukemic cells that, despite higher levels of BCR-ABL transcripts, exhibits innate insensitivity to IM. These cells remain after IM therapy, even when apparently complete responses are achieved, and they probably explain molecular disease persistence. Although it can be argued that patients may survive for many years with low levels of leukemia still present, it is possible to achieve disease clearance at the molecular level following an allogeneic stem cell transplantation. The emergence of drug resistance with IM monotherapy also argues in favor of complete disease eradication that we believe should remain the ultimate therapeutic goal in CML. New approaches to the elimination of these primitive CML cells may thus be crucial to the development of curative strategies.

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

“…2 Tyrosine kinase inhibitors (TKIs) have revolutionized the natural history of CML, with overall survival and event-free survival rates of 88% and 83%, respectively for imatinib-treated patients, and low frequency of transformation into blastic phase. 3 Quiescent primitive CML CD34 þ cells are insensitive to TKIs, however, and these cells persist even when complete responses are achieved, 4 leading to disease recurrence following discontinuation of TKIs in a fraction of CML patients. 5 The quiescent CML cells are in general resistant to a wide variety of proapoptotic stimuli, 6 implying unique mechanisms of protection from imatinib and other insults that induce apoptosis.…”

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

“…The cancer stem cell hypothesis has been substantiated and is exemplified in many types of leukemia, in which a stem or progenitor cell origin has been characterized [235,236]. In the case of BCR-ABL, accumulating evidence suggests that the target cell for transformation is a hematopoietic stem cell rather than a committed progenitor cell [65,237,238]. Interestingly, a recent study by Tothova et al, (2007) reported an elevated level of reactive oxygen species (ROS) restricted to the hematopoietic stem cell (HSC) compartment of mice deficient in three members of the FoxO subfamily (FoxO1, FoxO3 and FoxO4) [162].…”

“…Disturbingly, BCR-ABL transcripts coding for mutations in the kinase domain have been detected even in some patients who have achieved a complete cytogenetic response, suggesting a link between resistance and disease persistence [62,63]. Together with mathematical models that take into account the bi-phasic response to imatinib as well as a continued need for imatinib therapy [64], all these observations have led to the conclusion that imatinib is unable to target the quiescent BCR-ABL-positive stem cell population, and thus cannot completely eliminate the disease [65].…”

“…Unfortunately, it has been observed that while imatinib can eradicate the majority of proliferating CML progenitors and differentiated granulocytes, it is unable to target the minute population of quiescent CML stem cells [60,65,244]. In order to assess whether anti-neoplastics such as proteasome inhibitors will have long-term benefits in curing CML, it will be important to determine whether such compounds can target even those CML stem cells that persist during imatinib therapy.…”

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

“…The bone marrow microenvironment is believed to have a role in protecting LSCs and CML cells from TKIsinduced apoptosis (6). CXCL12, also called stromal cellderived factor-1 (SDF-1), a chemokine produced by bone marrow stromal cells (BMSC), signals through the cognate chemokine receptor CXCR4, which is broadly expressed by normal and malignant cells of hematopoietic and nonhematopoietic origin (7).…”