Secondary acute myeloid leukemia – a single center experience

Szotkowski, Tomáš; Rosenberger, Peter; Zapletalova, L; Sičová, Kateřina; Hubácek, J; Indrák, Karel

doi:10.4149/neo_2010_02_170

Cited by 25 publications

(20 citation statements)

References 16 publications

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“…ABCB1 over expression is a widely reported mechanism of cancer cell MDR, occurring in approximately 30% of AML patients 1[6]. About 70% of secondary AML patients also show up regulation in the ABCB1 gene expression 24. Cells exposed to ABCB1 substrate chemotherapeutics frequently demonstrate enhanced ABCB1 expression via multiple mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Genomic amplification of chromosome 7 in the Doxorubicin resistant K562 cell line

et al. 2018

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Acquisition of multi-drug resistance (MDR) is a major hindrance towards the successful treatment of cancers. Over expression of a range of ATP-dependent efflux pumps, particularly ABCB1 is a widely reported mechanism of cancer cell MDR. Approximately 30% acute myeloid leukemia (AML) patients demonstrate ABCB1 over expression. Several mechanisms for up regulation of ABCB1 have been proposed. Our aim was to investigate the role of genomic amplification of the chromosome 7 region with regard to its influence on ABCB1 over expression in AML cell line. For this, we developed Doxorubicin (Dox) resistant leukemic cell line from K562 cells, demonstrating MDR phenotype. The chromosomal changes associated with the acquisition of MDR were characterized by array-based comparative genomic hybridization (aCGH) with the parental K562 cell line as the reference genome. Significant genomic gains in the chromosomal region corresponding to 7q11.21-7q22.1 were observed in Dox selected cell line. Moreover, the amplicon contains the ABCB1 gene locus at 7q21.1 with a copy number gain of >4. ABCB1 mRNA was found to be up-regulated by54-fold. Our results demonstrate that the development of MDR in K562/Dox is underlined by a genomic amplification of the chromosome 7 region harboring the ABCB1 gene.

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Section: Discussionmentioning

confidence: 99%

Genomic amplification of chromosome 7 in the Doxorubicin resistant K562 cell line

et al. 2018

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“…AML-MRC is generally considered incurable without allogenic hematopoietic stem cell transplantation, and AML-MRC has an unfavorable prognosis because of a low probability of complete hematologic remission and a high possibility of leukemia relapse after chemotherapy. 14 In this study, we investigated the expression of CXCL12 in MDS/AML-MRC bone marrow to analyze the role of the hematopoietic niche in the pathogenesis of MDS. Understanding the interaction of hematopoietic cells with bone marrow niches should help in developing novel niche-targeted MDS therapies.…”

mentioning

confidence: 99%

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

Abe‐Suzuki

Kurata

Abe

et al. 2014

Laboratory Investigation

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The bone marrow microenvironment, known as 'hematopoietic stem cell niche,' is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12 þ cells were located in the cellular marrow or perivascular area, and were in contact with CD34 þ hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12 þ cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12 þ cell density than control bone marrow. CXCL12 þ cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34 þ hematopoietic cells of MDS bone marrow in contact with CXCL12 þ cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2 þ /CD34 þ cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12 þ cells constitute the niche for CD34 þ hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34 þ hematopoietic cells and disease progression in MDS. Thus, CXCL12 þ cells may represent a novel MDS therapeutic target.

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“…As compared to non-MRC AML, AML-MRC has, overall, been associated with inferior outcomes such as lower remission rates, ranging between 30-50%, and shorter overall survival [6,[19][20][21]. For AML-MRC patients able to receive intensive chemotherapy, the overall response rate (ORR) is 69%, with a complete response (CR) rate of 40-51% [21][22][23].…”

Section: Challenges In Treatment For Aml-mrc Patientsmentioning

confidence: 99%

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances

Koenig

Sahasrabudhe

Sigmund

et al. 2020

Genes

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Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25–34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9–12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin–cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group.

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Secondary acute myeloid leukemia – a single center experience

Cited by 25 publications

References 16 publications

Genomic amplification of chromosome 7 in the Doxorubicin resistant K562 cell line

Genomic amplification of chromosome 7 in the Doxorubicin resistant K562 cell line

CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances

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