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Papers by M. Van Den Heuvel-eibrink

Research paper thumbnail of 48 GATA2-RELATED Myelodysplastic Syndromes (MDS): Prevalence, Clinical Characteristics and Prognosis

Leukemia Research, 2015

loss of both Egr1 and Apc, two del(5q) genes, cooperate in the pathogenesis of MNs. Thus, alkylat... more loss of both Egr1 and Apc, two del(5q) genes, cooperate in the pathogenesis of MNs. Thus, alkylating agent therapy promotes the development of myeloid neoplasms in Egr1 +/-, Apc del/+ , p53 knockdown HSPCs. Our data supports the hypothesis that the prior treatment received by t-MN patients plays a central role in the expansion of rare mutant clones. We are currently unraveling the effects that alkylating agents have on HSPCs vs. the stromal microenvironment to gain an understanding of how the del(5q) cooperates with TP53 mutations in the pathogenesis of myeloid neoplasms.

Research paper thumbnail of PO-0771: Temporal changes in pediatric radiation oncology: DCOG LATER childhood cancer survivor study

Radiotherapy and Oncology, 2016

Research paper thumbnail of High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

Leukemia, 2010

Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently oc... more Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently occur in pediatric acute myeloid leukemia (AML). We recently reported differences in prognosis between the different translocation partners, suggesting differences in biological background. To unravel the latter, we used microarrays to generate gene expression profiles of 245 pediatric AML cases, including 53 MLLrearranged cases. Thereby, we identified a specific gene expression signature for t(9;11)(p22;q23), and identified BRE (brain and reproductive organ expressed) to be discriminative for t(9;11)(p22;q23) (Po0.001) when compared with other MLL subtypes. Patients with high BRE expression showed a significantly better 3-year relapse-free survival (pRFS) (80 ± 13 vs 30 ± 10%, P ¼ 0.02) within MLL-rearranged AML cases. Moreover, multivariate analysis identified high BRE expression as an independent favorable prognostic factor within pediatric AML for RFS (HR ¼ 0.2, P ¼ 0.04). No significant differences were identified for 3-year event-free survival or for 3-year overall survival. Forced expression of BRE did not result in altered cell proliferation, apoptosis or drug sensitivity, which could explain the favorable outcome. In conclusion, overexpression of the BRE gene is predominantly found in MLL-rearranged AML with t(9;11)(p22;q23). Although further investigation for the role of BRE in leukemogenesis and outcome is warranted, high BRE expression is an independent prognostic factor for pRFS in pediatric AML.

Research paper thumbnail of 232 Relevance of WT1 expression, mutations and single nucleotide polymorphisms in juvenile myelomonocytic leukemia

Research paper thumbnail of 232 Relevance of WT1 expression, mutations and single nucleotide polymorphisms in juvenile myelomonocytic leukemia

Research paper thumbnail of 233 IER3 in childhood myelodysplastic syndrome

Leukemia Research, 2011

Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role... more Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role in the apoptose and the NF-úb pathway. Recently it was shown that IER3 aberrations are recurrent genetic abnormalities found in a subset of adult patients with myelodysplastic syndrome (MDS) and altered expression is found even in patients without a chromosome 6 aberration. Furthermore a low IER3 expression is associated with a worse outcome. Aim: To investigate the role of IER3 in the pathogenesis of childhood MDS. Methods: Quantitative real-time PCR was performed in 58 childhood MDS patients of which 16 carried a chromosome 6 aberration. The data were compared to the expression levels of the bone marrow of 8 healthy controls. Furthermore methylation specific PCR was performed to investigate hypermethylation of the promotorregion of the IER3 gene. Results: 72% (42/58) of the childhood MDS patients showed a >4-fold decrease in IER3 expression compared with the mean of healthy controls (MWU p = 0.05). There was no difference in expression between patients with or without a chromosome 6 aberration. of which 3 had a breakpoint in the IER3 region. The three patients, who carried a breakpoint in the IER3 region, did not show different expression. Patients with the lowest IER3 expression showed the worst survival rate. Conclusion: Downregulation of the IER3 expression is common in childhood MDS, even in patients without chromosome 6 aberrations and this influences the outcome. The downregulation of the IER3 expression is not regulated by hypermethylation of the IER3 promotorregion. As in adult MDS, further analyses are necessary to reveal the role of IER3 in the pathobiology of childhood MDS.

Research paper thumbnail of 233 IER3 in childhood myelodysplastic syndrome

Leukemia Research, 2011

Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role... more Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role in the apoptose and the NF-úb pathway. Recently it was shown that IER3 aberrations are recurrent genetic abnormalities found in a subset of adult patients with myelodysplastic syndrome (MDS) and altered expression is found even in patients without a chromosome 6 aberration. Furthermore a low IER3 expression is associated with a worse outcome. Aim: To investigate the role of IER3 in the pathogenesis of childhood MDS. Methods: Quantitative real-time PCR was performed in 58 childhood MDS patients of which 16 carried a chromosome 6 aberration. The data were compared to the expression levels of the bone marrow of 8 healthy controls. Furthermore methylation specific PCR was performed to investigate hypermethylation of the promotorregion of the IER3 gene. Results: 72% (42/58) of the childhood MDS patients showed a >4-fold decrease in IER3 expression compared with the mean of healthy controls (MWU p = 0.05). There was no difference in expression between patients with or without a chromosome 6 aberration. of which 3 had a breakpoint in the IER3 region. The three patients, who carried a breakpoint in the IER3 region, did not show different expression. Patients with the lowest IER3 expression showed the worst survival rate. Conclusion: Downregulation of the IER3 expression is common in childhood MDS, even in patients without chromosome 6 aberrations and this influences the outcome. The downregulation of the IER3 expression is not regulated by hypermethylation of the IER3 promotorregion. As in adult MDS, further analyses are necessary to reveal the role of IER3 in the pathobiology of childhood MDS.

Research paper thumbnail of Repeats in the kringle IV encoding domains in the Apo(a) gene and serum lipoprotein(a) level do not contribute to the risk for avascular necrosis of the bone (AVN) in pediatric acute lymphoblastic leukemia

Research paper thumbnail of JAK2 V617F mutation is a rare event in juvenile myelomonocytic leukemia

Leukemia, 2007

Taken together, the data reported by Cazzaniga et al. and our results consistently show that in p... more Taken together, the data reported by Cazzaniga et al. and our results consistently show that in pediatric patients, NPM1 mutations are less common than in adults and tend to affect older patients. Preliminary data also indicate that NPM1 mutations might be associated with favorable outcome, which warrants further studies to address this question. In addition, our results point to an effect of age on the prevalence of different NPM1-mutations, with non-typical (i.e. non-type A) mutations being most prevalent in children and younger adults. The reason for this association is unknown, but might refer to different molecular mechanisms involved in the development of this abnormality, a process which is currently largely unclear. This finding has also important implications for the MRD analysis and molecular follow-up of pediatric cases with NPM1 þ AML. Whereas in adults, type A mutations predominate and assays focusing on this type will be suitable in most cases, in pediatric patients mutations should always be analyzed by sequencing. In these cases, a recently reported LNA-based procedure might be advantageous for follow-up of residual disease after treatment.

Research paper thumbnail of HLA-identical umbilical cord blood transplantation from a sibling donor in juvenile myelomonocytic leukemia

Research paper thumbnail of Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Research paper thumbnail of Applicability and evaluation of a psychosocial intervention program for childhood cancer patients

Supportive Care in Cancer, 2015

Purpose The purpose of this study is to explore the applicability of a psychosocial intervention ... more Purpose The purpose of this study is to explore the applicability of a psychosocial intervention in childhood cancer patients. Methods This individualized structured psychosocial program to enhance social-emotional functioning and coping with disease-related effects includes six sessions for children and two sessions for parents. This program was part of a combined intervention with physical exercise. Questionnaires are used to evaluate completion of the psychosocial intervention, coping and satisfaction with the psychosocial intervention by patients and psychologists, and ranking of the individual topics by patients, parents, and psychologists. Results Of the 30 patients (mean age 13.0 (SD 3.0); 53.3 % male; 30 % still on treatment) who participated in the psychosocial intervention, two dropped out due to medical complications and one due to lack of time; 90 % completed the psychosocial intervention. Overall, patients liked participation in the intervention (4.2 on a 5-point scale; SD 0.8) and were positive about the psychologists (8.1 on a 10-point scale; SD 1.3). Psychologists rated the intervention on several points (e.g., clarity of the manual and content of the intervention), and mean scores ranged from 7.1 (SD 1.1) to 8.6 (SD 0.9) on 10-point scales. Minor adaptations were suggested by patients and psychologists, including customizing according to age and a more patient-tailored approach. Conclusion This psychosocial intervention for childhood cancer patients appears to be applicable. Future studies need to establish whether this intervention combined with a physical exercise intervention actually improves psychosocial functioning of childhood cancer patients. When proven effective, this combined intervention can be offered to childhood cancer patients and may enhance their physical health and quality of life.

Research paper thumbnail of 48 GATA2-RELATED Myelodysplastic Syndromes (MDS): Prevalence, Clinical Characteristics and Prognosis

Leukemia Research, 2015

loss of both Egr1 and Apc, two del(5q) genes, cooperate in the pathogenesis of MNs. Thus, alkylat... more loss of both Egr1 and Apc, two del(5q) genes, cooperate in the pathogenesis of MNs. Thus, alkylating agent therapy promotes the development of myeloid neoplasms in Egr1 +/-, Apc del/+ , p53 knockdown HSPCs. Our data supports the hypothesis that the prior treatment received by t-MN patients plays a central role in the expansion of rare mutant clones. We are currently unraveling the effects that alkylating agents have on HSPCs vs. the stromal microenvironment to gain an understanding of how the del(5q) cooperates with TP53 mutations in the pathogenesis of myeloid neoplasms.

Research paper thumbnail of PO-0771: Temporal changes in pediatric radiation oncology: DCOG LATER childhood cancer survivor study

Radiotherapy and Oncology, 2016

Research paper thumbnail of High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

Leukemia, 2010

Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently oc... more Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently occur in pediatric acute myeloid leukemia (AML). We recently reported differences in prognosis between the different translocation partners, suggesting differences in biological background. To unravel the latter, we used microarrays to generate gene expression profiles of 245 pediatric AML cases, including 53 MLLrearranged cases. Thereby, we identified a specific gene expression signature for t(9;11)(p22;q23), and identified BRE (brain and reproductive organ expressed) to be discriminative for t(9;11)(p22;q23) (Po0.001) when compared with other MLL subtypes. Patients with high BRE expression showed a significantly better 3-year relapse-free survival (pRFS) (80 ± 13 vs 30 ± 10%, P ¼ 0.02) within MLL-rearranged AML cases. Moreover, multivariate analysis identified high BRE expression as an independent favorable prognostic factor within pediatric AML for RFS (HR ¼ 0.2, P ¼ 0.04). No significant differences were identified for 3-year event-free survival or for 3-year overall survival. Forced expression of BRE did not result in altered cell proliferation, apoptosis or drug sensitivity, which could explain the favorable outcome. In conclusion, overexpression of the BRE gene is predominantly found in MLL-rearranged AML with t(9;11)(p22;q23). Although further investigation for the role of BRE in leukemogenesis and outcome is warranted, high BRE expression is an independent prognostic factor for pRFS in pediatric AML.

Research paper thumbnail of 232 Relevance of WT1 expression, mutations and single nucleotide polymorphisms in juvenile myelomonocytic leukemia

Research paper thumbnail of 232 Relevance of WT1 expression, mutations and single nucleotide polymorphisms in juvenile myelomonocytic leukemia

Research paper thumbnail of 233 IER3 in childhood myelodysplastic syndrome

Leukemia Research, 2011

Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role... more Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role in the apoptose and the NF-úb pathway. Recently it was shown that IER3 aberrations are recurrent genetic abnormalities found in a subset of adult patients with myelodysplastic syndrome (MDS) and altered expression is found even in patients without a chromosome 6 aberration. Furthermore a low IER3 expression is associated with a worse outcome. Aim: To investigate the role of IER3 in the pathogenesis of childhood MDS. Methods: Quantitative real-time PCR was performed in 58 childhood MDS patients of which 16 carried a chromosome 6 aberration. The data were compared to the expression levels of the bone marrow of 8 healthy controls. Furthermore methylation specific PCR was performed to investigate hypermethylation of the promotorregion of the IER3 gene. Results: 72% (42/58) of the childhood MDS patients showed a >4-fold decrease in IER3 expression compared with the mean of healthy controls (MWU p = 0.05). There was no difference in expression between patients with or without a chromosome 6 aberration. of which 3 had a breakpoint in the IER3 region. The three patients, who carried a breakpoint in the IER3 region, did not show different expression. Patients with the lowest IER3 expression showed the worst survival rate. Conclusion: Downregulation of the IER3 expression is common in childhood MDS, even in patients without chromosome 6 aberrations and this influences the outcome. The downregulation of the IER3 expression is not regulated by hypermethylation of the IER3 promotorregion. As in adult MDS, further analyses are necessary to reveal the role of IER3 in the pathobiology of childhood MDS.

Research paper thumbnail of 233 IER3 in childhood myelodysplastic syndrome

Leukemia Research, 2011

Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role... more Background: IER3, a gene located on chromosome 6p21, encodes for a glycoprotein that plays a role in the apoptose and the NF-úb pathway. Recently it was shown that IER3 aberrations are recurrent genetic abnormalities found in a subset of adult patients with myelodysplastic syndrome (MDS) and altered expression is found even in patients without a chromosome 6 aberration. Furthermore a low IER3 expression is associated with a worse outcome. Aim: To investigate the role of IER3 in the pathogenesis of childhood MDS. Methods: Quantitative real-time PCR was performed in 58 childhood MDS patients of which 16 carried a chromosome 6 aberration. The data were compared to the expression levels of the bone marrow of 8 healthy controls. Furthermore methylation specific PCR was performed to investigate hypermethylation of the promotorregion of the IER3 gene. Results: 72% (42/58) of the childhood MDS patients showed a >4-fold decrease in IER3 expression compared with the mean of healthy controls (MWU p = 0.05). There was no difference in expression between patients with or without a chromosome 6 aberration. of which 3 had a breakpoint in the IER3 region. The three patients, who carried a breakpoint in the IER3 region, did not show different expression. Patients with the lowest IER3 expression showed the worst survival rate. Conclusion: Downregulation of the IER3 expression is common in childhood MDS, even in patients without chromosome 6 aberrations and this influences the outcome. The downregulation of the IER3 expression is not regulated by hypermethylation of the IER3 promotorregion. As in adult MDS, further analyses are necessary to reveal the role of IER3 in the pathobiology of childhood MDS.

Research paper thumbnail of Repeats in the kringle IV encoding domains in the Apo(a) gene and serum lipoprotein(a) level do not contribute to the risk for avascular necrosis of the bone (AVN) in pediatric acute lymphoblastic leukemia

Research paper thumbnail of JAK2 V617F mutation is a rare event in juvenile myelomonocytic leukemia

Leukemia, 2007

Taken together, the data reported by Cazzaniga et al. and our results consistently show that in p... more Taken together, the data reported by Cazzaniga et al. and our results consistently show that in pediatric patients, NPM1 mutations are less common than in adults and tend to affect older patients. Preliminary data also indicate that NPM1 mutations might be associated with favorable outcome, which warrants further studies to address this question. In addition, our results point to an effect of age on the prevalence of different NPM1-mutations, with non-typical (i.e. non-type A) mutations being most prevalent in children and younger adults. The reason for this association is unknown, but might refer to different molecular mechanisms involved in the development of this abnormality, a process which is currently largely unclear. This finding has also important implications for the MRD analysis and molecular follow-up of pediatric cases with NPM1 þ AML. Whereas in adults, type A mutations predominate and assays focusing on this type will be suitable in most cases, in pediatric patients mutations should always be analyzed by sequencing. In these cases, a recently reported LNA-based procedure might be advantageous for follow-up of residual disease after treatment.

Research paper thumbnail of HLA-identical umbilical cord blood transplantation from a sibling donor in juvenile myelomonocytic leukemia

Research paper thumbnail of Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Research paper thumbnail of Applicability and evaluation of a psychosocial intervention program for childhood cancer patients

Supportive Care in Cancer, 2015

Purpose The purpose of this study is to explore the applicability of a psychosocial intervention ... more Purpose The purpose of this study is to explore the applicability of a psychosocial intervention in childhood cancer patients. Methods This individualized structured psychosocial program to enhance social-emotional functioning and coping with disease-related effects includes six sessions for children and two sessions for parents. This program was part of a combined intervention with physical exercise. Questionnaires are used to evaluate completion of the psychosocial intervention, coping and satisfaction with the psychosocial intervention by patients and psychologists, and ranking of the individual topics by patients, parents, and psychologists. Results Of the 30 patients (mean age 13.0 (SD 3.0); 53.3 % male; 30 % still on treatment) who participated in the psychosocial intervention, two dropped out due to medical complications and one due to lack of time; 90 % completed the psychosocial intervention. Overall, patients liked participation in the intervention (4.2 on a 5-point scale; SD 0.8) and were positive about the psychologists (8.1 on a 10-point scale; SD 1.3). Psychologists rated the intervention on several points (e.g., clarity of the manual and content of the intervention), and mean scores ranged from 7.1 (SD 1.1) to 8.6 (SD 0.9) on 10-point scales. Minor adaptations were suggested by patients and psychologists, including customizing according to age and a more patient-tailored approach. Conclusion This psychosocial intervention for childhood cancer patients appears to be applicable. Future studies need to establish whether this intervention combined with a physical exercise intervention actually improves psychosocial functioning of childhood cancer patients. When proven effective, this combined intervention can be offered to childhood cancer patients and may enhance their physical health and quality of life.