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Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed. [ABSTRACT FROM AUTHOR]

Cases of pediatric acute myeloid leukemia (AML) with complex karyotypes including chromosome 5 abnormalities are rare and have a very poor prognosis. Management of AML with monosomy 5/del(5q) has been inconsistent. We treated three adolescents with this AML subtype using combined low-dose cytarabine and mitoxantrone, concurrently with decitabine and G-CSF, for remission induction. Decitabine was also included in the conditioning regimen before hematopoietic cell transplantation (HCT). All three patients achieved complete remission after treatment with this combination therapy. The treatment was well tolerated, and the patients are alive and free of disease at 3.6, 3.2, and 3.0 years after HCT, respectively. [ABSTRACT FROM AUTHOR]

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q). [ABSTRACT FROM AUTHOR]

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q).

Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%-25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that the knockdown of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knockdown, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53., Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A 70-year-old male was referred to our hospital for marked thrombocytosis without anemia. The patient simultaneously presented with an MPL W515L mutation, one of the major driver mutations in essential thrombocythemia (ET), and deletion of 5q, a characteristic cytogenetic abnormality in myelodysplastic syndrome (MDS). Bone marrow examination showed a combination of both mature hyperlobulated megakaryocytes, as found in ET, and small hypolobulated megakaryocytes, typically found in MDS with del(5q). The present case is consistent with the recently proposed category of myeloid neoplasms with isolated del(5q) and an MPN driver mutation. [ABSTRACT FROM AUTHOR]

Keywords: Myelodysplastic syndromes; del(5q); non-del(5q); mutations; lenalidomide EN Myelodysplastic syndromes del(5q) non-del(5q) mutations lenalidomide e133 e137 5 05/19/20 20200515 NES 200515 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterised by ineffective haematopoiesis leading to peripheral blood cytopenias and an increased risk of transformation to acute myeloid leukaemia (AML) (Haferlach I et al. i , [5]; Makishima I et al. i , [8]). Lenalidomide (LEN) has been approved for the treatment of patients with del(5q) low-risk MDS and transfusion dependence. We collected 74 samples from patients with MDS at diagnosis or treatment-naïve with LEN follow-up treatment of two or more cycles; 32 patients presented with del(5q), while 42 patients did not have del(5q) in their karyotype (Table S1). As expected, responders were mainly classified in MDS with isolated del(5q) (71%), while non-responders were enriched in MDS with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD; 33%), and MDS with multilineage dysplasia (MDS-MLD; 26%; Table 1). 1 TableClinical characteristics of the patients. [Extracted from the article]

Abstract Background Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. Methods We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. Results A total of 33.9, 34.3, and 31.8% patients were aged

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized by peripheral blood cytopenia and dishematopoiesis and frequently progress to acute myeloid leukemia. Genetic defects play a major role in pathogenesis of MDS, including cytogenetic abnormalities, gene mutations, and abnormal gene expression. Chromosomal abnormalities have been detected in approximately 50–60% of MDS patients, including the deletions of chromosome 5q and 7q, trisomy 8, and complex karyotypes. Newer genomic technologies, such as single-nucleotide polymorphism array and next-generation sequencing, revealed the heterozygous deletions resulting in haploinsufficient gene expression (e.g., CSNK1A1, DDX41 on chromosome 5, CUX1, LUC7L2, EZH2 on chromosome 7) involved in the pathogenesis of MDS. In addition, recurrent somatic mutations in more than 50 genes have been identified in 80–90% of MDS. The most recurrent genetic mutations are involved in the RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, DDX41) and epigenetic modifications, such as histone modification (e.g., ASXL1, EZH2) and DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2). TP53 mutation is associated with aggressive disease and frequently coincides with deletion of chromosome 5q. This review summarizes the recent progress in molecular pathogenesis of MDS. A better understanding of the specific subgroups of MDS patients will also aid in the development of new therapeutic approach for MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40–45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel 'biallelic TP53 inactivation' (also called 'multi-hit TP53') MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults' MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations. [ABSTRACT FROM AUTHOR]

TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.

Objective: The most typical cytogenetic aberration in myelodysplastic syndromes is del(5q), which, when isolated, is associated with refractory anaemia and good prognosis. Based on high rates of erythroid response and transfusion independence, Lenalidomide (LEN) became the standard treatment. This multi- centre study was designed to supplement Italian Registry data on LEN by addressing prescription, administration appropriateness, haematological and cytogenetic responses and disease evolution. Methods: MORE study was an observational, non- interventional, multi- centre, retrospective and prospective study. Cases were recruited from 45 Haematological Centres throughout Italy. Data were collected from the Italian National Registry for Lenalidomide administration and supplemented by a MORE data form. Results: Data from 190/213 patients were analysed. In all, 149 had been diagnosed by conventional cytogenetics (GROUP A) and 41 only by FISH (GROUP B). Overall erythroid response was obtained in 92.8% of cases. Overall cytogenetic remission was achieved in 22.6% of cases. Disease progression occurred in 15.6% of cases. Clonal cytogenetic evolution characterised progression to AML but not to higher risk MDS. Conclusions: Erythroid response to Lenalidomide was similar in MDS with isolated del(5q) and with del(5q) plus one anomaly. Progression to AML or higher risk MDS showed different cytogenetic features. [ABSTRACT FROM AUTHOR]

The myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematologic stem cell disorders with the characteristic of ineffective hematopoiesis leading to low blood counts, and a risk of progression to acute myeloid leukemia (AML). To understand specific molecular characteristics of different MDS subtypes with del(5q), we analyzed the gene expression profiles of CD34+ cells from MDS patients of different databases and its enriched pathways. 44 genes, such as MME and RAG1, and eight related pathways were identified to be commonly changed, indicating their conserved roles in MDS development. Additionally, U43604 was identified to be specifically changed in three subtypes with del(5q), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) and refractory anemia with excess blasts (RAEB). C10orf10 and CD79B were specifically changed in RA patients with del(5q), while POU2AF1 were in RARS patients with del(5q). We also analyzed specific pathways of MDS subtypes, such as “Glycosaminoglycan biosynthesis-chondroitin sulfate” which was specific identified in RARS patients. Importantly, those findings can be validated well using another MDS database. Taken together, our analysis identified specific genes and pathways associated with different MDS subtypes with del(5q). [ABSTRACT FROM AUTHOR]

Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS-del(5q) patients undergoing LEN therapy for a median of 6 cycles. Therapy with LEN led to a significant increase in the median absolute lymphocyte count (1.3-fold, p = 0.013) without changes in the distribution of the T helper cells within the entire compartment. In parallel, the frequency of Treg increased significantly during treatment both in the peripheral blood (5.0 vs. 9.6 %, p = 0.001) and bone marrow (3.4 vs. 8.1 %, p = 0.001). Surprisingly, LEN treatment led to a decrease in TGFbeta levels, both in the peripheral blood (4.9 vs. 2.3 ng/ml, p = 0.039) and bone marrow (4.5 vs. 0.8 ng/ml, p = 0.023). These changes were not associated with an increase in pro-inflammatory Th17 cells. Taken together, our results demonstrate that LEN induces a shift in lymphocytic populations towards immunosuppression in MDS-del(5q) patients. [ABSTRACT FROM AUTHOR]

Loss of a section of the long arm of chromosome 5, as a sole cytogenetic abnormality, characterizes a rare type of myelodysplastic syndrome [del(5q) MDS] and the co-existence of the JAK2 V617F mutation occurs in a small subset of these cases. Patients with isolated del(5q) MDS have a relatively favorable prognosis, with transformation to acute myeloid leukemia occurring in <10%, and their disease responds well to lenalidomide. However the optimal therapeutic approach for patients with del(5q) MDS in coexistence with the JAK2 V617F mutation, which is common to myeloproliferative neoplasms, remains to be elucidated. The present study reports a 77-year-old, transfusion-dependent female patient diagnosed with del(5q) MDS and a concomitant JAK2 V617F mutation. The patient was started on 10 mg lenalidomide daily for 21 days in a 28 day-cycle and within the first month of treatment, the patient became transfusion-independent. The only toxicity observed was grade 3 neutropenia, which was managed with transient treatment discontinuation and dose reduction on restart (5 mg). The patient achieved a complete cytogenetic and molecular response (normal karyotype and undetected JAK2 V617F mutation) within 6 months of treatment. However, 12 months post treatment initiation and while on hematological, cytogenetic and molecular response, the patient was unwilling to continue on treatment and lenalidomide was discontinued. The patient remains in hematological response, which lasts for >5 years despite treatment discontinuation. The present case highlights the coexistence of the JAK2 V617F mutation in del(5q) MDS and suggests that lenalidomide treatment is beneficial and effective for these patients, leading to complete hematological, cytogenetic and molecular response. Hematological response may be sustained for long periods of time, even following the discontinuation of the treatment. [ABSTRACT FROM AUTHOR]

Mutations of CSNK1A1, a gene mapping to the commonly deleted region of the 5q- syndrome, have been recently described in patients with del(5q) myelodysplastic syndromes ( MDS). Haploinsufficiency of Csnk1a1 in mice has been shown to result in β-catenin activation and expansion of haematopoietic stem cells ( HSC). We have screened a large cohort of 104 del(5q) MDS patients and have identified mutations of CSNK1A1 in five cases (approximately 5%). We have shown up-regulation of β-catenin target genes in the HSC of patients with del(5q) MDS. Our data further support a central role of CSNK1A1 in the pathogenesis of MDS with del(5q). [ABSTRACT FROM AUTHOR]

Background: Lenalidomide has been approved for the treatment of lower-risk myelodysplastic syndrome (MDS) with 5q deletion (del(5q)). We present for the first time a retrospective analysis of low-risk MDS with isolated del5q treated with lenalidomide, outside the clinical trials. Methods: 36 red blood cell (RBC) transfusion-dependent patients have been included in the study. Patients received lenalidomide 10 mg/day on days 1-21 of 28-day cycles. Results: 91.7 % of patients responded to lenalidomide treatment: 72.2 % achieved erythroid response, 19.4 % achieved minor erythroid response and 8.4 % of patients did not respond to treatment. Response depended on number of previous treatment lines (p = 0.0101), International Prognostic System Score (IPSS; p = 0.0067) and RBC transfusion frequency (p = 0.0139). Median duration of response was 16 months (range 6-60 months). Treatment was well tolerated. We observed hematological toxicity (grade 3 and 4): neutropenia in 16 (44.4 %) patients and thrombocytopenia in 9 (25 %) patients. Two patients (5.5 %) progressed to high-risk MDS and two subsequent progressed to acute myeloid leukemia. A Kaplan-Meier estimate for overall survival at 5 years in the study group was 79.0 ± 8.8 %. Conclusions: Lenalidomide in this group of patients was beneficial for the treatment of RBC transfusion-dependency with well-known safety profile. [ABSTRACT FROM AUTHOR]

Objectives Lenalidomide is a potent drug with pleiotropic effects in patients with myelodysplastic syndrome ( MDS) with deletion of the long arm of chromosome 5 [del(5q)]. We investigated its effect on regulation of micro RNA (mi RNA) expression profiles in del(5q) patients with MDS in vivo. Methods We used mi RNA expression microarrays to study changes in mi RNA levels in peripheral blood CD14+ monocytes collected from patients before and during lenalidomide treatment and compared them with those from healthy donors. Results Before treatment, we observed strong upregulation of pro-apoptotic miR-34a and miR-34a* that diminished during lenalidomide exposure. Upregulation of HOX-related miR-196b and erythroid-specific miR-451 seen in untreated patients remained unchanged after the treatment. At the time of hematologic response, expression of several mi RNAs clustering to the 14q32 locus was reduced. Additionally, we focused more deeply on mi RNAs from the 5q commonly deleted region and found that levels of miR-378 and miR-378* followed haploinsufficiency trend. Conclusions This report describes changes in mi RNA expression in del(5q) patients with MDS treated with lenalidomide, likely arising from deregulation of pathways implicated in lenalidomide action. [ABSTRACT FROM AUTHOR]

Lenalidomide is a novel thalidomide analogue with immunomodulatory and antiangiogenic effects that has been successfully used for the treatment of low and intermediate-1 risk myelodysplastic syndromes (MDSs) with a del(5q) aberration. Because information about the influence of lenalidomide on the microRNA (miRNA) transcriptome is limited, we performed miRNA expression profiling of bone marrow CD34+ cells obtained from MDS patients with the del(5q) abnormality who had been subjected to lenalidomide treatment. To define differences in miRNA expression, we performed paired data analysis to compare the miRNA profiles of patients before and during lenalidomide treatment and those of healthy donors. The analysis showed that miRNAs clustering to the 14q32 region had a higher expression level in patient samples before treatment than in the healthy control samples, and this elevated expression was diminished following lenalidomide administration. Because some of the 14q32 miRNAs play important roles in hematopoiesis, stem cell differentiation, and apoptosis induction, the expression of this cluster may be associated with the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Lenalidomide induces in patients with myelodysplastic syndrome (MDS) and del(5q) erythroid and cytogenetic response rates as high as 75% and 50%, respectively. It is still unclear, however, how long lenalidomide treatment should be continued and whether or not the drug could be interrupted. To assess the feasibility of lenalidomide discontinuation, we revised a cohort of 16 low-risk MDS patients with del(5q) treated at our institute in a phase II multicentric Italian study. Among the 12 responding patients, four discontinued lenalidomide while in complete response. All four patients needed during treatment a permanent lenalidomide reduction from 10 to 5 mg/day because of haematological toxicity (three patients) or grade 3 muscular and bone pain (one patient). At lenalidomide discontinuation after 16, 20, 27 and 20 months from the start, respectively, all four patients were in complete hematologic response and three forth in complete cytogenetic response. Three patients are still in response after 36, 30 and 20 months from lenalidomide discontinuation, respectively: The remaining patient relapsed after 20 months, and she is now receiving a new course of lenalidomide. In conclusion, long-lasting remissions are achievable in MDS patients with del(5q) in complete response after lenalidomide discontinuation. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective A subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System ( IPSS)-defined Low-/ Intermediate ( Int)-1-risk myelodysplastic syndromes ( MDS) with isolated del(5q). Methods Patients received lenalidomide 10 mg/d (days 1-21; n = 47) or 5 mg/d (days 1-28; n = 43) on 28-d cycles or placebo ( n = 45). From the placebo and lenalidomide 5 mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10 mg at 16 wk, respectively. Results Rates of red blood cell-transfusion independence ( RBC- TI) ≥182 d were higher in the lenalidomide 10 mg (57.4%; P < 0.0001) and 5 mg (37.2%; P = 0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major + minor responses) were 56.8% ( P < 0.0001), 23.1% ( P = 0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10 mg, 5 mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC- TI ≥182 d vs. non-responders ( P = 0.0072). The most common grade 3-4 adverse event was myelosuppression. Conclusions These data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/ Int-1-risk MDS with isolated del(5q). [ABSTRACT FROM AUTHOR]

The concomitant presence of del(5q) and JAK2V617F mutation is an infrequent event which occurs in rare patients with peculiar cytogenetic, molecular, morphological and clinical features, resembling those of both myelodysplastic syndromes and myeloproliferative neoplasms. Lenalidomide may induce rapid, profound, and long-lasting responses in a subset of these patients. However, the mechanism(s) by which the drug acts in these conditions remain not completely elucidated. A new case report and a review of all cases published so far in this setting are provided. Furthermore, the possibility of categorizing - from a clinical, pathological, and biological point of view - for at least some of these patients as a potential distinct entity is discussed. [ABSTRACT FROM AUTHOR]

Abstract: Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9g/dL was associated with poorer TFS (p =0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets <100,000mm−3 and Lenalidomide treatment retained the statistical significant impact. LFS at 2 and 5 years was 86% and 73% respectively, and median time to sAML was 8.16 years (CI 95%: 6.05–10.27). In the multivariate analysis only thrombocytopenia retained statistical significance. In summary, this retrospective study show that level of Hb is an important parameter in order to determine the time until TD, it should be also stressed the importance of an early treatment in order to prevent TD development and shorter survival. [Copyright &y& Elsevier]

In lower-risk myelodysplastic syndromes (MDS) with del(5q), lenalidomide induces erythroid responses associated with better survival. In a phase II, single-arm trial, 45 patients with anemia and lower-risk del(5q) MDS received lenalidomide 10 mg/day to evaluate quality of life (QoL) changes, measured by QOL-E, safety, responses and survival. Lenalidomide was well tolerated, with 80% completing ≥ 24 weeks of treatment. Earlier study discontinuation was related to disease progression ( n = 5), death ( n = 1) and withdrawal of consent ( n = 3). Within 24 weeks, 82% obtained erythroid responses, durable in 69% at 52 weeks. Cytogenetic responses occurred in 29 patients (64%), with 10 patients achieving a complete cytogenetic response. QoL-E scores correlated with hemoglobin levels and improved in erythroid responders. Erythroid responders had an 86% reduced risk of disease progression and an 80% reduction in mortality risk compared with non-responders. These findings corroborate earlier studies and give further support to the use of lenalidomide in lower-risk MDS and del(5q). [ABSTRACT FROM AUTHOR]

The current World Health Organization classification considers myelodysplastic syndrome with isolated del(5q) a distinct entity owing to its characteristic clinical and pathologic features. Recently, several studies have examined survival, leukemic transformation, and various prognostic factors in these patients. However, there is a lack of detailed comparative pathologic analysis of myelodysplastic syndrome cases in which del(5q) is present in association with additional cytogenetic abnormalities. We studied 26 cases of myelodysplastic syndrome at initial diagnosis with 5q- alone, 5q- plus 1 additional abnormality, and 5q- as part of a complex karyotype. Four of 17 patients had evidence of JAK2 V617F mutation. In contrast to cases of myelodysplastic syndrome with isolated 5q-, patients with additional abnormalities had normal mean corpuscular volume and decreased platelet counts (P < .001). Based on bone marrow examination, they were significantly more likely to have increased cellularity, trilineage dysplasia, lower proportion of small hypolobated megakaryocytes, higher number of blasts, and fibrosis. The presence of these morphologic features can be used to distinguish these more aggressive cases from those with myelodysplastic syndrome with isolated 5q- and a more benign clinical course. [ABSTRACT FROM AUTHOR]

Abstract: Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by peripheral cytopenias in the face of normo- or hypercellular, dysplastic bone marrow that arise from mutations in the hematopoietic stem/progenitor cell (HSPC). The disease is characterized by multiple cytogenetic and molecular defects, which result in an extremely heterogeneous phenotype. Recently, significant efforts have been made to develop appropriate mouse models to study this complex disease. Because of the heterogeneity of MDS, no single model is able to capture the MDS phenotype in its entirety. In this review, we describe several MDS mouse models and discuss the advances made in our understanding of the different disease mechanisms within the malignant clone and the marrow microenvironment. In addition, we describe progress in xenotransplantation models of MDS and discuss questions that remain to be answered. [Copyright &y& Elsevier]

In T-cell acute lymphoblasic leukemia (T-ALL), neoplastic chromosomal rearrangements are known to deregulate members of the homeobox gene families NKL and HOXA. Here, analysis of T-ALL cell lines and primary cells identified aberrant expression of a third homeobox gene group, the Paired (PRD) class. LOUCY cells revealed chromosomal deletion at 5q31, which targets the downstream regulatory region of the PRD homeobox gene PITX1, removing a STAT1 binding site. STAT1 mediates repressive interleukin 2 (IL2)--STAT1 signaling, implicating IL2 pathway avoidance as a possible activation mechanism. Among primary T-ALL samples, 2/22 (9%%) aberrantly expressed PITX1, highlighting the importance of this gene. Forced expression of PITX1 in JURKAT cells and subsequent target gene analysis prompted deregulation of genes involved in T-cell development including HES1, JUN, NKX3-1, RUNX1, RUNX2, and TRIB2. Taken together, our data show leukemic activation of PITX1, a novice PRD-class homeobox gene in a subset of early-staged T-ALL, which may promote leukemogenesis by inhibiting T-cell development. [ABSTRACT FROM AUTHOR]

Abstract: The microRNA/miR system might contribute to deregulation of cell homeostasis/disease phenotype. This is the first approach to generate an expression profile of 365 microRNAs in myelodysplastic syndromes (MDS) with normal karyotype (n =12) and distinct cytogenetic aberrations (n =12). In MDS-del(5q), a series of microRNAs not in the 5q-region was increased. MicroRNAs encoded on chromosomes 5, 7 and 8 were not differentially expressed in MDS with del(5q), −7 or +8. Evaluation in a larger cohort could confirm the up-regulation of the miR-1 in MDS. These findings provide evidence that MDS-haematopoiesis is distinct in its microRNA-expression pattern from non-neoplastic cells. [ABSTRACT FROM AUTHOR]

Background: Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with chromosome 5q deletion [del(5q)]. Methods: To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. Results: After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 ± 2.5 g/dL (up to a mean 11.8 ± 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05–0.31) to 12 wk 204.71-fold (2.86–446.32; P < 0.0001). Conclusions: These observations in the patient setting support the importance of RPS14 in the pathogenesis of MDS with del(5q). [ABSTRACT FROM AUTHOR]

Abstract: During the past few years our understanding of the genetic basis for the myelodysplastic syndromes (MDS) has improved significantly. A few subgroups have been studied in detail and the genetic alterations are now to a great extent revealed. In 5q- syndrome haploinsufficiency of the ribosomal gene RPS14 appears to cooperate with loss of two micro-RNAs miR-145 and miR-146 to induce key features of the disease. Some mutations are specific for certain categories of MDS while others, such as TET2 seem to occur across the various categories. JAK2 mutations are mainly found in patients with myeloproliferative characteristics. The prognostic implications of most of the novel mutations are not yet fully understood, moreover, functional studies are required in order to understand the interplay between the different lesions; how they give rise to the disease and how some may lead to disease evolution including leukemic transformation. An improved understanding of the pathophysiology of MDS may lead to the identification of suitable targets for future drug development. [Copyright &y& Elsevier]

Myelodysplastic syndromes (MDS) are a group of hematopoietic stem cell disorders characterized by refractory cytopenias and susceptibility to leukemic transformation. On a subset of MDS patients with deletion of the long arm of chromosome5 (del(5q)), lenalidomide exerts hematological and cytogenetic effects, but the underlying pharmacological mechanisms are not fully understood. In this study, we have investigated the in vitro effects of lenalidomide on an MDS-derived cell line, MDS-L, which carries del(5q) and complex chromosome abnormalities. We found that the growth of MDS-L cells was specifically suppressed mainly by apoptosis, and in addition, multinucleated cells were frequently formed and finally died out in the presence of lenalidomide. Time-lapse microscopic observation and the DNA ploidy analysis revealed that lenalidomide does not affect DNA synthesis but inhibits cytokinesis of MDS-L cells. The gene expression profile showed decreased expression of M phase-related genes such as non-muscle myosin heavy-chain 10, polo-like kinase 1, aurora kinase B, citron kinase and kinesin family member 20A(KIF20A). Interestingly, KIF20A is located at 5q31. These data contribute to the understanding of action mechanisms of lenalidomide on MDS with del(5q) and complex abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: To determine the clinical utility of FISH for del(5q) in MDS/AML, we first compared FISH for 5q31 (EGR1) and 5q33 (CSF1R) in 51 myeloid neoplasms containing del(5q) by metaphase cytogenetics. Next, EGR1 FISH was compared to metaphase cytogenetics alone in 269 cases of known or suspected MDS/AML. These studies show that while metaphase cytogenetics alone can detect del(5q) in most cases, FISH is particularly useful in cases with suboptimal growth. EGR1 FISH detects del(5q) in a broad variety of myeloid neoplasms, including at least most cases of 5q− syndrome, while studies for CSF1R add little to the diagnostic yield. [Copyright &y& Elsevier]

Anemia remains the most challenging clinical manifestation to treat in patients with lower-risk myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents are widely used to treat anemia in such patients, but less than one third respond to these agents, and the duration of response is often limited. Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality. Lenalidomide also has meaningful clinical activity in lower-risk patients without deletion 5q. The experience with lenalidomide in MDS is a modern example of reciprocal translational research, in which bench work led to an approved drug for patients, and clinical observations led to better understanding of the mechanism of action of the drug itself and even more understanding of the biology of the underlying disease. This article reviews the clinical experience with lenalidomide, highlighting recent understanding of the dual karyotype-dependent mechanisms of action. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a group of haematopoietic stem cell disorders that pose a unique challenge for gene expression profiling by virtue of their inherent heterogeneity. Despite monoclonality of MDS, the marrow picture is complicated by the presence of not only stromal cells but also by varying stages of differentiating diseased cells belonging to all three lineages. Now that reproducible results can be obtained from nanograms of RNA, it is possible to derive useful information from even a limited number of cells; for example, dysregulation of ribosomal and translational genes was detected in MDS patients compared to controls using a small number of CD34+ cells. Gene expression profiling in MDS patients treated with lenalidomide or 5-azacitidine+thalidomide yielded signatures which differentiated responders from non-responders. These biologic and clinical insights are providing the framework on which to build a new model of these diseases which, despite their heterogeneity, manifest certain unifying themes. [Copyright &y& Elsevier]

Optimal management of patients with myelodysplastic syndromes (MDS) requires an insight into the biology of the disease and the mechanisms of action of the available therapies. This review focuses on low-risk MDS, for which chronic anaemia and eventual progression to acute myeloid leukaemia are the main concerns. We cover the updated World Health Organization classification, the latest prognostic scoring system, and describe novel findings in the pathogenesis of 5q− syndrome. We perform in depth analyses of two of the most widely used treatments, erythropoietin and lenalidomide, discussing mechanisms of action, reasons for treatment failure and influence on survival. [ABSTRACT FROM AUTHOR]

All-trans-retinoic acid (ATRA) alone or in combination with cytokines and vitamins has been shown to stimulate erythropoiesis in low-risk myelodysplastic syndromes (MDS). We performed a phase II study on 29 patients with MDS and isolated del(5q) including bands q31-q33 to determine the efficacy and safety of ATRA in combination with tocopherol-a. All patients had low/intermediate-1 risk MDS according to the international prognostic scoring system. They received 45 mg/m2 ATRA on days 1 to 90, and 90 mg/m2 on days 91 to 180. Tocopherol dosage was 600 IU three times daily. Twenty-four patients completed dose level I, and 12 patients dose level II. Eighty-six percent of patients experienced side effects. Thirty discontinued the drug treatment due to such events as skin reactions, cheilitis, conjunctivitis, joint pain, creatinine increase, or CNS symptoms. One patient (3%) achieved a major erythroid response resulting in transfusion independence throughout the study. Four patients (14%) achieved a minor erythroid response with>50% reduction of transfusion needs. None of the participants had a cytogenetic response. There was no significant improvement in quality of life among responding patients as measured by the European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire. Based on these results, the combination of ATRA and tocopherol-a is not recommended for the treatment of del(5q) MDS. [ABSTRACT FROM AUTHOR]