In the largest published case series

In the largest published case series, Rossi et al. identified seven cases of infant B-ALL, including three cases of congenital leukemia, with lineage switch from B-lymphoid to myelomonocytic leukemia [12]. An additional two cases were described with a switch from AML M5 to B-ALL. Of the nine described cases with lineage switch, seven had detectable MLL rearrangements. These cases were identified from 1482 cases of pediatric leukemia in the authors’ institution, which suggested an incidence of 0.6%. A recent meta-analysis of lineage switched pediatric leukemias identified 18 such cases reported, of which five were congenital acute leukemia; all five had MLL rearrangements detectable [13]. RT-PCR positive, FISH negative MLL rearrangements have been described previously [14]. Large scale recombinome studies of MLL rearranged leukemia has identified a mechanism for such cases which involves either a fragment of the MLL gene being inserted elsewhere in the genome, or a fragment of a locus being inserted proximally to the MLL gene [15]. Both circumstances would create a copy-neutral MLL-fusion oncogene that would not be detectable with break apart FISH testing or chromosomal microarrays. Mechanisms that would explain lineage switch have been proposed and include a bipotential progenitor, de-differentiation, and preferential proliferation of a minor clone not detectable at diagnosis [12]. An interesting recent case of lineage switch involving a MLL rearranged infant leukemia, occurred following treatment with CD19 directed chimeric antigen receptor T-cells [16]. In this case, an IgH rearrangement present in the original leukemia was not present in the relapsed myeloid blasts despite an identical MLL rearrangement found in both. This suggests that a bipotential progenitor with a germline IgH locus was the founder clone.
Introduction Leukemia, a type of blood cancer, originates from abnormal hematopoietic stem nampt inhibitor and results in a high number of abnormal white blood cells. Chemotherapy, using cytotoxic drugs to destroy cancer cells, has been the most effective treatment. However, multidrug resistance (MDR), the ability of cancer cells to survive exposure to many chemotherapeutic drugs, is the major problem in cancer treatment. Recent studies have revealed that overexpression of drug transporter proteins, such as P-glycoprotein (P-gp), is associated with resistance to multiple chemotherapeutic drugs [1,2]. P-gp is a 170kDa transmembrane protein encoded by the MDR1 gene. It functions as a pump to remove anticancer drugs from cells, thereby leading to drug resistance. As reported, P-gp is overexpressed in several drug-resistant cancer cell lines [3–5]. Thus, P-gp might potentially be a key molecule in MDR cancer. However, the regulatory mechanism of this protein was not elucidated. CD147 is a protein in the immunoglobulin superfamily group [6–9]; it promotes many properties of cancer cells, including multidrug resistance [10–12]. A number of studies have shown the high expression level and involvement of CD147 in many MDR cell lines [13,14]. These studies suggested that CD147 plays an important role in regulating resistance to anticancer drugs. However, the regulatory mechanism of CD147 on the P-gp in leukemic cells remains unclear.
Materials and methods
Results
Discussion There are several mechanisms of MDR, including decreased drug uptake, reduced intracellular drug concentration by efflux pumps, or altered cell-cycle checkpoints [18–20]. Among these, overexpression of P-gp, ATP-binding cassette (ABC) drug transporters, is an important mechanism [1,2]. P-gp is a transmembrane glycoprotein that is widely expressed in many human cancers [21]. Levels of P-gp have been correlated with drug resistance in several different cancers [1,2,20,22]. Therefore, understanding MDR is important to help patients for reducing or preventing chemotherapy resistance. CD147 is a type I transmembrane glycoprotein of the immunoglobulin superfamily. CD147 has been reported to regulate the expression of P-gp and affect apoptosis in cancer cells with MDR phenotype [10,13,14]. In the present study, drug-free K562/ADR was first established by culturing K562/ADR in medium without Adriamycin for at least five months. Then Adriamycin drug sensitivities of both drug-resistant and drug-free K562/ADR cells were determined and compared by MTT assay. The results showed that Adriamycin was more cytotoxic in drug-free K562/ADR cells than drug-resistant K562/ADR cells. Moreover, the drug-resistant K562/ADR cell line presented high expression levels of P-gp and CD147, suggesting that both proteins are associated with the MDR phenotype in leukemic cells. This finding is in line with previous studies that have demonstrated high levels of mRNA and protein expression of MDR1 and CD147 in MDR cancer cell lines [13]. Recent studies have revealed CD147 is responsible for the altered multidrug resistance to P-gp substrate drugs [14]. Up-regulation of MDR1 at both transcription and expression levels was found in CD147-transfected MCF7 breast cancer cells, which promotes multidrug resistance to P-gp substrate drugs. In addition, silencing of CD147 led to increase chemosensitivity in MDR cancer cell lines [23,24]. As previously mentioned, the linkage exists among CD147 and P-gp in leukemia with MDR were further investigated. Drug-resistant K562/ADR cells were co-cultured with MEM-M6/6 anti-CD147 mAb, and then P-gp and CD147 expression were determined by Western blotting and semi-quantitative RT-PCR. The MEM-M6/6 antibody decreased the expression of P-gp and CD147 proteins and mRNA levels, suggesting the regulation of P-gp expression by CD147 molecule in the association of multidrug resistant phenotype in K562/ADR cells. As previously reported, the CD147 molecule contains different bioactive domains responsible for cell functions [25]. Therefore, activation of bioactive domains, by specific mAbs or its natural ligands, induces different cellular responses [25]. MEM-M6/6 was reported as a CD147 mAb, which recognized the membrane-proximal domain of the CD147 molecule [26]. These results suggest that the membrane-proximal domain of the CD147 molecule may be a particular domain that is responsible for the regulation of multidrug resistance. Furthermore, triggering CD147 with MEM-M6/6 decreased the expression of CD147, which in turn down-regulated P-gp expression.