scholarly journals Impact of PPM1D Mutations in Patients with Myelodysplastic Syndrome and Deletion of Chromosome 5q

2021 ◽  
Author(s):  
Victoria Panagiota ◽  
Manja Meggendorfer ◽  
Anne Sophie Kubasch ◽  
Razif Gabdoulline ◽  
Jan Krönke ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Chromosome 5Q

A decade of progress in myelodysplastic syndrome with chromosome 5q deletion

Leukemia ◽  
2018 ◽  
Vol 32 (7) ◽  
pp. 1493-1499 ◽  
Author(s):  
Alan List ◽  
Benjamin L. Ebert ◽  
Pierre Fenaux
Keyword(s):  
Myelodysplastic Syndrome ◽  
Chromosome 5Q ◽  
5Q Deletion

scholarly journals Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion

Haematologica ◽  
2009 ◽  
Vol 95 (3) ◽  
pp. 406-414 ◽  
Author(s):  
M. Ximeri ◽  
A. Galanopoulos ◽  
M. Klaus ◽  
A. Parcharidou ◽  
K. Giannikou ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Chromosome 5Q ◽  
5Q Deletion

Degradation of TRAF6 by Bortezomib-Induced Autophagy Contributes to Cell Death in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2452-2452
Author(s):  
Jing Fang ◽  
Lyndsey Bolanos ◽  
Garrett Rhyasen ◽  
Carmen Rigolino ◽  
Agostino Cortelezzi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
26S Proteasome ◽  
Negative Regulator ◽  
Myeloid Malignancies ◽  
Chromosome 5Q ◽  
Acute Myeloid

Abstract Abstract 2452 Deletion of chromosome 5q in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients results in loss of miR-146a, which is a negative regulator of the innate immune pathway by targeting TNF receptor associated factor-6 (TRAF6). Therefore, MDS and AML patients with reduced miR-146a expression concomitantly exhibit elevated TRAF6 protein. TRAF6 is an E3 ubiquitin ligase that catalyzes K63-linked polyubiquitin chains on substrates that lead to pathway activation, one of which includes NF-kB. Mice lacking miR-146a, or with overexpression of TRAF6, develop AML- and MDS-like features. Bortezomib (Velcade©), which shows promise alone or in combination with chemotherapy in certain groups of MDS and AML patients, is a selective and reversible inhibitor of the 26S proteasome. Studies on the mechanism of action of Bortezomib have shown that pro-apoptotic proteins are stabilized following proteasome inhibition and contribute to the anti-cancer effect. In this report, paradoxically, we find that Bortezomib induces rapid and complete degradation of TRAF6 protein, but not mRNA, in MDS/AML cell lines and human CD34+ cells. A similar finding was observed when AML cells were treated with MG132, another proteasome inhibitor, indicating that degradation of TRAF6 is secondary to proteasomal inhibition. Interestingly, the reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, as indicated by conversion of LC3B-I to LC3B-II and degradation of SQSTM1/p62, and subsequently with apoptosis in MDS/AML cells. Addition of an autophagy inhibitor (3-methyladenine [3-MA]) to Bortezomib-treated AML cells maintained TRAF6 protein expression and enhanced cell viability. Similarly, TRAF6 degradation was blocked by 3-MA when cells were treated with Rapamycin, an mTOR inhibitor and inducer of autophagy. These findings suggest that a mechanism of Bortezomib-induced cell death in myeloid malignancies involves elimination of TRAF6 protein by autophagosomes. Forced expression of TRAF6 in two AML cell lines partially blocked the cytotoxic effect of Bortezomib, suggesting that TRAF6 is an important target of Bortezomib. To determine whether loss of TRAF6 is sufficient to impede growth of MDS and AML, we used a genetic approach to inhibit TRAF6 in MDS/AML cell lines and bone marrow cells from MDS patients with deletion of chromosome 5q. RNAi-mediated depletion of TRAF6 in MDS and AML samples resulted in impaired malignant hematopoietic stem/progenitor function and rapid apoptosis. To uncover the molecular consequences following loss of TRAF6, we applied gene expression profiling and identified genes relevant to the survival of MDS and AML cells. In summary, these findings implicate TRAF6 in Bortezomib-induced cell death and in the maintenance of myeloid malignancies, and reveal a novel mechanism of TRAF6 regulation through autophagic degradation. Disclosures: Oliva: Celgene: Consultancy.

scholarly journals Durable Hematological and Major Cytogenetic Response in a Patient with Isolated 20q Deletion Myelodysplastic Syndrome Treated with Lenalidomide

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Bagi Jana ◽  
Anas Khanfar ◽  
Mary Ninan
Keyword(s):  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Significant Risk ◽  
Cytogenetic Response ◽  
Antiangiogenic Activity ◽  
Meaningful Activity ◽  
Chromosome 5Q ◽  
Risk Of Progression ◽  
Bone Marrow Disorder ◽  
5Q Deletion

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective hematopoiesis. It is characterized by peripheral blood cytopenia and significant risk of progression to acute myeloid leukemia result. Deletion of the long arm of chromosome 20 (20q deletion) is present in 3–7% of patients with MDS. Lenalidomide is an immunomodulatory agent with antiangiogenic activity. It is FDA approved for the treatment of anemia in patients with low or int-1 risk MDS with chromosome 5q deletion with or without additional cytogenetic abnormalities. Study of lenalidomide in patients with MDS without 5q deletion but other karyotypic abnormalities demonstrated meaningful activity in transfusion dependent patients; however, response of patients with isolated 20q deletion to lenalidomide is not known. We are reporting a patient with 20q deletion MDS treated with lenalidomide after he failed to respond to azacytidine; to our knowledge this is the first report of a patient with isolated 20q deletion treated with lenalidomide.

scholarly journals Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion

Oncogene ◽  
2012 ◽  
Vol 32 (9) ◽  
pp. 1110-1120 ◽  
Author(s):  
S Wei ◽  
X Chen ◽  
K McGraw ◽  
L Zhang ◽  
R Komrokji ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Chromosome 5Q ◽  
5Q Deletion

L-Leucine Improves the Anemia of DBA and the 5q- Syndrome Via Activation of the mTOR Pathway in a p53-Independent Manner

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1257-1257
Author(s):  
Nirmalee Abayasekara ◽  
Anupama Narla ◽  
Slater Hurst ◽  
Hong Sun ◽  
Maria Virgilio ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Ribosomal Proteins ◽  
Mrna Translation ◽  
Mtor Pathway ◽  
Zebrafish Embryos ◽  
P53 Expression ◽  
Human Cd34 ◽  
Chromosome 5Q ◽  
Cd34 Cells ◽  
Shrna Knockdown

Abstract Abstract 1257 Haploinsufficiency of ribosomal proteins (RP) has been shown to be the common basis for the anemia observed in ribosomopathies such as Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q (del(5q) MDS). DBA is a congenital bone marrow failure syndrome characterized by a profound macrocytic anemia. More than half the patients with DBA have been shown to have a heterozygous loss of an RP gene, with RPS19 being the most frequently mutated. The “5q- syndrome” is a subtype of myelodysplastic syndrome (MDS) also characterized by severe anemia that is caused by heterozygous loss of the RPS14 gene on chromosome 5q. The p53 pathway is known to play a critical role in the pathophysiology of the ribosomopathies. The leading hypothesis is that ribosomal haploinsufficiency leads to disrupted ribosome biogenesis with an accumulation of free ribosomal proteins that bind MDM2. MDM2 is an E3 Ubiquitin ligase that normally binds to and targets p53 for proteosomal degradation. The consequent accumulation of p53 leads to cell cycle arrest and apoptosis, which ultimately results in anemia. Several animal models have shown that the anemia associated with RP haploinsufficiency is almost completely alleviated in a p53 null background. However, we and others have shown that p53-independent pathway(s) also contribute to the anemia associated with RP haploinsufficiency. We have previously modeled DBA and del (5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14 respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. We have further demonstrated that treatment of Rps19 and Rps14 deficient embryos with the amino acid L-Leucine, a known activator of mRNA translation, results in a marked improvement in anemia. This observation was confirmed in primary human CD34+ cells, following shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that L-leucine treatment activates the mTOR pathway in zebrafish embryos deficient in Rps19 or Rps14. In order to determine if the effect of L-Leucine on RP deficient erythroid cells is p53 dependent, we injected rps19 and rps14 morpholinos into zebrafish embryos and treated them with L-Leucine. Total RNA was collected 48hpf and evaluated for expression of p53 by qPCR analysis. As expected, the expression of p53 and its downstream targets (p21 and PUMA) were upregulated in Rps14 and Rps19 deficient embryos. P53 expression levels remained elevated even after L-Leucine treatment. Levels of p21, a direct transcriptional target of p53, remained unchanged in L-Leucine treated RP deficient zebrafish embryos; however, expression of PUMA increased following L-Leucine treatment. The expression of the PUMA gene has previously been shown to have a p53-independent regulatory component. Preliminary studies in the A549 cell line, which harbors wild type p53, also showed increased levels of p53 expression upon shRNA mediated downregulation of both RPS19 and RPS14, which remained unaltered following L-Leucine treatment. These observations are currently being confirmed in primary human CD34+ cells, following shRNA knockdown of RPS19 and RPS14. Our preliminary studies show that the effect of L-Leucine in improving the anemia in models of DBA and del(5q) MDS occurs independently of p53. This supports our hypothesis that the erythroid phenotype in these disorders has a p53-independent component. Our finding that L-Leucine treated RP deficient cells are likely to express elevated rather than diminished levels of p53 in spite of improved anemia also has important implications for the clinical management of patients, since p53 inactivation is associated with tumor growth. A trial using L-Leucine for patients with DBA will be opening soon in the United States. Disclosures: Ebert: Celgene: Consultancy; Genoptix: Consultancy.

Very short-term lenalidomide treatment associated with durable resolution of anemia in a patient with myelodysplastic syndrome with chromosome 5q deletion

2011 ◽  
Vol 91 (2) ◽  
pp. 309-310 ◽  
Author(s):  
Laura Cannella ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Giuseppina Loglisci ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Short Term ◽  
Chromosome 5Q ◽  
5Q Deletion

scholarly journals Efficacy and safety of lenalidomide in patients with myelodysplastic syndrome with chromosome 5q deletion

2012 ◽  
Vol 3 (2) ◽  
pp. 105-116 ◽  
Author(s):  
Vu H. Duong ◽  
Rami S. Komrokji ◽  
Alan F. List
Keyword(s):  
Myelodysplastic Syndrome ◽  
Specific Effect ◽  
Phase Iii ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Phase Iii Trial ◽  
Chromosome 5Q ◽  
Cycle Arrest ◽  
Fda Approval ◽  
Large Phase

Myelodysplastic syndrome (MDS) with del(5q) is a unique hematopoietic stem cell disease that typically follows an indolent course and demonstrates particular sensitivity to lenalidomide, a second-generation immunomodulatory agent. Early trials demonstrated rapid and durable responses leading to US Food and Drug Administration (FDA) approval in 2005. Definitive confirmatory evidence from a large phase III trial was recently published. Other recent advances include a better understanding of the pathogenesis of disease including haplodeficiency of several candidate genes, and elucidation of the lenalidomide-specific effect on two phosphatases ultimately leading to p53 degradation in the erythroid progenitors and cell cycle arrest in earlier myeloid progenitors. In this review, we describe the pathogenesis of MDS with del(5q), summarize the major clinical studies establishing the activity of lenalidomide in this population, discuss commonly encountered adverse events, and shed light on practical uses of this agent in the clinic.

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