Key Points DPPIV (CD26) is a new specific marker of CML LSC that aids CML diagnostics and the measurement, characterization, and purification of LSC. DPPIV on CML LSC degrades SDF-1 and thereby promotes the niche-escape of LSC, which may contribute to extramedullary myeloproliferation in CML.

In most patients with systemic mastocytosis (SM), including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V. KIT D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive drug target.

IntroductionChronic myeloid leukemia (CML) is a myeloproliferative disease in which leukemic cells exhibit the reciprocal translocation t(9;22) and the bcr/abl oncogene. [1][2][3] The resulting oncoprotein, BCR/ABL, displays constitutive tyrosine kinase activity and activates a number of signaling molecules including RAS/RAF/MAP kinases, the phosphoinositide 3-kinase (PI3-kinase), and signal transducer and activator of transcription 5 (STAT5). [4][5][6][7][8] In addition, BCR/ABL converts cytokine-dependent cell lines to growth factor independence and acts oncogenic in mice. 9 Several different mechanisms have been implicated in BCR/ ABL-dependent growth and accumulation of leukemic cells in CML. [10][11][12] One important mechanism may be inhibition of apoptosis. 10,[13][14][15][16] Thus, a number of antiapoptotic molecules are expressed in CML cells and may contribute to enhanced survival of leukemic cells. [10][11][12][13][14][15][16][17] Likewise, it has been shown that CML cells express several members of the BCL-2 family including BCL-2, BCL-x L , or A1. [13][14][15][16][17] However, the relative contribution of each of these molecules to inhibition of apoptosis in CML cells has not been defined yet. In addition, some of these molecules may only be expressed in leukemic cells in a subgroup of patients. 17 MCL-1 is a well-characterized member of the BCL-2 family that is considered to act antiapoptotic in various neoplastic cells including several leukemia-derived cell lines. [18][19][20][21] Originally, MCL-1 was described as a survival-enhancing molecule that is expressed during 12-O-tetra decanoyl phorbol 13-acetate (TPA) induced differentiation of leukemic ML-1 cells. 18 The CML-derived cell line K562 has also been described to express the MCL-1 protein. 19,[21][22][23] However, little is known so far about expression of MCL-1 in primary CML cells, the regulation of expression of MCL-1 in these cells, and the role that this antiapoptotic molecule may play in survival and accumulation of leukemic cells in patients with CML.In the present study, we have investigated the role of BCR/ABL in expression of MCL-1 in leukemic cells and analyzed underlying signaling pathways. The results of our study show that primary CML cells express MCL-1 in a constitutive manner and that BCR/ABL promotes the expression of MCL-1 through activation of the RAS/RAF/MAP kinase pathway. Moreover, our data show that down-regulation of MCL-1 by antisense oligonucleotides (ASOs) counteracts growth Patients, materials, and methods ConstructsPlasmids used in this study were pDCR-ras-G12V 24,25 (kindly provided by Yoel Kloog, Hadassah Medical Center, Jerusalem, Israel), pMT-Ha-ras-N17 26 (kindly provided by Mark Ewen, Dana Farber Cancer Institute, Boston, MA), and pBSK-mcl-1 27,28 (kindly provided by Stanley J. Korsmeyer, Dana Farber Cancer Institute). cDNAs were cloned into pcDNA3.1 ϩ vector (Invitrogen, Carlsbad, CA). The mcl-1 reporter gene construct (mcl-1-Luc) 29 was a kind gift from Steven W. Edwards (School of Biological Sciences...