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World J Stem Cells. Jun 26, 2012; 4(6): 44-52
Published online Jun 26, 2012. doi: 10.4252/wjsc.v4.i6.44
Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy
Xavier Thomas
Xavier Thomas, Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, 69495 Pierre Benite, France
Xavier Thomas, Claude Bernard Lyon I University, INSERM U590, 69008 Lyon, France
Author contributions: Thomas X solely contributed to this paper.
Correspondence to: Xavier Thomas, MD, PhD, Department of Hematology, Lyon-Sud Hospital, 69495 Pierre Benite cedex, France. xavier.thomas@chu-lyon.fr
Telephone: +33-4-78862235 Fax: +33-4-72678880
Received: September 21, 2011
Revised: March 8, 2012
Accepted: March 15, 2012
Published online: June 26, 2012

Leukemia stem cells (LSCs), which constitute a minority of the tumor bulk, are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal. The presence of LSCs has been demonstrated in acute lymphoblastic leukemia (ALL), of which ALL with Philadelphia chromosome-positive (Ph+). The use of imatinib, a tyrosine kinase inhibitor (TKI), as part of front-line treatment and in combination with cytotoxic agents, has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL. New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations. An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs, such as nilotinib and dasatinib. However, in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells. None of the TKIs in clinical use target the LSC. Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs. Allogeneic stem cell transplantation (SCT) remains the only curative treatment available for these patients. Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations. Hence, TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy. Better understanding the biology of Ph+ ALL will open new avenues for effective management. In this review, we highlight recent findings relating to the question of LSCs in Ph+ ALL.

Keywords: Acute lymphoblastic leukemia, Philadelphia chromosome, Tyrosine kinase inhibitors, Leukemia stem cells, Prognosis