Deletion of the multidrug resistance protein 1 (MRP1) gene in acute myeloid leukemia patients with inversion 16: expression of MRP1 homologues

Vries, Elisabeth G.E. de; Vellenga, Edo

doi:10.1038/sj.leu.2401949

Cited by 6 publications

(7 citation statements)

References 4 publications

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“…It is well established that there are often deletions 3Ј from MYH11, involving a region of 160-350 kb centromeric to the 16p13 short-arm inversion breakpoint cluster region. 5,6,24 However, we found 2 examples of deletions telomeric to the CBFB breakpoint cluster region at band 16q22. For both of these deletion patients, it is noteworthy that each had an unusually unfavorable disease course.…”

Section: Discussionmentioning

confidence: 64%

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

Kolomietz

Al-Maghrabi

Brennan

et al. 2001

Blood

199

171

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BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia ؉ (Ph ؉ ) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5 region of ABL and the 3 region of the BCR genes on the 9q ؉ chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph ؉ CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3 regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15; 17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. IntroductionSince the discovery of the Philadelphia (Ph) chromosome in patients with chronic myelogenous leukemia (CML), it has become evident that specific chromosomal rearrangements are consistently associated with hematologic malignancies. 1 Although it is well established that such recurrent chromosome translocations generate several different types of pathognomic fusion oncogenes, the precise details of the molecular processes leading to these rearrangements in leukemias are poorly understood.The Ph chromosome arises from a reciprocal translocation of the long arms of chromosomes 9 and 22 that transposes the 3Ј segment of the ABL gene from 9q34 to the 5Ј segment of the BCR gene on 22q11. The resulting BCR-ABL gene is transcribed into a chimeric messenger RNA and then translated into fusion proteins of varying size (p190 bcr-abl , p210 bcr-abl , and p230 bcr-abl ), depending on the location of the breakpoint of the genes involved. Although these BCR/ABL chimeric fusion proteins play a central role in the pathogenesis of CML, it is unclear whether these fusion oncoproteins alone are sufficient to explain the full range of clinical responses to the disease process. 2 Recently it was proposed that extensive submicroscopic deletions, 5Ј of ABL and 3Ј of BCR, on the derivative chromosome 9 could often accompany BCR/ABL rearrangement and that the disease associated with a deletion was more refractil...

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Section: Discussionmentioning

confidence: 64%

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

Kolomietz

Al-Maghrabi

Brennan

et al. 2001

Blood

199

171

View full text Add to dashboard Cite

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“…These findings emphasize that the resistance mediated by drug efflux pumps is a complex phenomenon and might provide a plausible explanation for the disappointing results of the clinical use of a specific inhibitor of only one transporter protein. 33,34 Moreover, it has been demonstrated that the inhibition or absence of one transporter protein might force or induce the activity of additional transporters, 35,36 which may further limit the effectivity of the selective inhibition of transporter proteins.…”

Section: Discussionmentioning

confidence: 99%

Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia

Kolk

Vellenga

Scheffer

et al. 2002

Blood

107

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“…A similar observation was observed in AML patients with the chromosomal inversion 16; patients with deletion of MRP1 showed upregulation of other MRP genes. 42 Some studies have been conducted with PSC833 as sole MDR modifier in relapsed AML patients. 52,53 Considering the results of the present study, which show a diversity of changes in MDR genes, it seems highly unlikely that one MDR modifier will overcome multidrug resistance in AML.…”

Section: Discussionmentioning

confidence: 99%

“…We have described a correlation between the lack of MRP activity and the occurrence of MRP1 deletions in AML patients with an inversion on chromosome 16 in a previous study. 42 We therefore determined in the present study the karyotype of the AML patients at diagnosis and at relapse, with emphasis on the chromosomal loci 16p13 and 7q21, on which MRP1 and MDR1 are located. Thirty paired samples of de novo and refractory or relapsed state AML were studied.…”

Section: Introductionmentioning

confidence: 99%

Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia

et al. 2001

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The multidrug resistance proteins (MRPs) MRP1, MRP2, MRP3, MRP5 and P-glycoprotein (P-gp) act in concert with each other to give a net resultant pump function in acute myeloid leukemia (AML). The aim of the present study was to analyze the activity of these proteins, which might be upregulated at relapse as compared with de novo AML due to clonal selection. The mRNA expression and activity of P-gp and the MRPs were determined with RT-PCR and flow cytometry, in conjunction with phenotype, as measured with the monoclonal antibodies CD34, CD38 and CD33, in 30 paired samples of de novo and relapsed AML. P-gp and MRP activity varied strongly between the cases (rhodamine 123 efflux-blocking by PSC833: 5.4 ؎ 7.7, and carboxyfluorescein efflux-blocking by MK-571: 4.3 ؎ 6.7, n ‫؍‬ 60). P-gp and MRP activity were increased in 23% and 40% of the relapse samples, and decreased in 30% and 20% of the relapse samples, respectively (as defined by a difference of Ͼ2 ؋ standard deviation of the assays). Up-or downregulation of mRNA expression was observed for MDR1 (40%), MRP1 (20%), MRP2 (15%), MRP3 (30%), and MRP5 (5%). Phenotyping demonstrated a more mature phenotype in 23% of the relapsed AML cases, and a more immature phenotype in 23% of the relapses, which was independent of the karyotypic changes that were observed in 50% of the studied cases. P-gp and MRP activity correlated with the phenotypic changes, with higher P-gp and MRP activities in less mature cells (r ‫؍‬ −0.66, P Ͻ 0.001 and r ‫؍‬ ؊0.31, P ‫؍‬ 0.02, n ‫؍‬ 58). In conclusion, this study shows that P-gp and MRP activity are not consistently upregulated in relapsed AML. However, P-gp and MRP activities were correlated with the maturation stage as defined by immune phenotype, which was observed to be different in 46% of the relapses. Leukemia (2001) 15, 1544-1553.

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Deletion of the multidrug resistance protein 1 (MRP1) gene in acute myeloid leukemia patients with inversion 16: expression of MRP1 homologues

Cited by 6 publications

References 4 publications

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia

Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia

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