Academic literature on the topic 'Myelodisplasia'

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Abstract Abstract 4977 Introduction Lenalidomide (Len) is an immunomodulatory drug that has a selective inhibitory effect on the del(5q) clone. The exact mechanism of action has not been defined: Len is known to have multiple biologic activities and an impressive effect on myelodysplasia (MDS) with deletion of the long arm of chromosome 5, leading to transfusion-independence, a complete erythroid and cytogenetic response in over 65% of cases. Similar responses were also seen in patients with MDS and a complex karyotype including del(5q), which usually have a poor prognosis. Lenalidomide leads to an important myelotoxicity in 50% of patients, so the optimal schedule merits discussion. In this report we describe unexpected erythroid and cytogenetic responses in two elderly patients with del(5q) MDS treated with Len for less than 12 wks. Case Reports Since November 2008 we have been treating two female patients with a diagnosis of MDS and a deletion of the long arm of chromosome 5 [del(5q)] with Len. Both patients had a low-int-1 IPSS risk. At the time of diagnosis severe cardio-pulmonary co-pathologies were present, therefore we observed a very bad tolerance to anaemia. The monthly transfusion requirement before starting treatment was 6 packed RBC units. Len was started at a full dose (10 mg/d for 21 days every 4 wks). Patient 1 received a diagnosis of “5q- syndrome” (Fig. 1). She stopped therapy after only 10 days due to severe agitation and panic attacks; however, one month later we observed a progressive reduction of transfusion need. Two months later, the patient was transfusion-free and the response had been ongoing for 6 months; she obtained a very good partial cytogenetic response. After 6 months the anaemia worsened again; we started Len 10 mg/d, but after 15 days the therapy was stopped due to the same side effects. Forty days later, we observed transfusion-independence for another 6 months, and a very good partial cytogenetic response. When the patient's condition worsened again, she was treated with Len 10 mg on alternative days with a better tolerance. After the first cycle, she presented the same side effects. Again the karyotype analysis showed a very good partial cytogenetic response. In Patient 2 the morphologic analysis was compatible with RAEB-1 and the cytogenetic analysis showed a [del(16)(q22)] together with del (5q) (Fig. 2). Len was stopped after 15 days due to renal impairment, cardiopulmonary and cardiac failure; she was then given only palliative therapy, but four wks later she achieved a complete erythroid response and remained transfusion-free for one year. In January 2010 the patient worsened and started Len again (10 mg/d for 21 dd every 4 wks) with good tolerance, a complete hematologic response and a very good partial cytogenetic response. Hematologic responses are illustrated in Tab. 1 and Tab. 2. In these two patients, after a very short treatment with Len we observed a complete erythroid response and a very good partial cytogenetic response. The median time to achieve the response was 6 wks (range 4–8 weeks). Transfusion-independence was durable (24 and 38 weeks respectively). Discussion Giagounidis et al (Ann. Hematol, 2007) describe two similar cases in which short-time Len treatment was given and a good response was obtained. One of our patients experienced grade III hematologic toxicity during the first cycle of therapy; despite this, we did not observe severe infectious or hemorrhagic complications. Despite the very short duration of Len treatment in our two patients, in both cases we achieved a very good partial cytogenetic response. Conclusions We observed unexpected effects of Len in myelodysplastic patients with del(5q) and a low-int1 IPSS risk who were treated for a very short period; additionally, this response was observed again at least twice when treatment was begun again: although these patients obviously represent only selected cases, the good erythroid and cytogenetic responses suggest that some patients with MDS and del(5q) may benefit from Len treatment even if this must be discontinued. Disclosures: No relevant conflicts of interest to declare.

Patients with ≥ 20% <30% bone marrow blast infiltration previously regarded as a transitional category between myelodisplasia and acute myeloid leukemia (AML) according to FAB classification, have been subsequently included into AML WHO classification. However, controversies still remain as to whether the natural history and responsiveness to therapy of these patients is comparable to that of patients with > 30% BM blast AML. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%-30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥ 65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to hypomethilating agents such as azacitidine and decitabine. These agents have shown efficacy, with reduced toxicity as compared with IC, when administered to elderly patients not eligible for IC and with 20-30% BM blasts and multilineage dysplasia. Future randomized clinical trials are eagerly awaited to determine whether hypomethylating agents can substitute for IC even in elderly patients with good functional status.

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract Background: The treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in the absence of H. pylori infection or when the lymphoma fails to regress after adequate antibiotic treatment remains controversial. Fludarabine (F) is an active agent for indolent lymphoma, however, its clinical activity in gastric MALT lymphoma has not been studied. The aim of the study is to assess the efficacy and safety of single-agent fludarabine in gastric MALT lymphoma and to analyze the molecular response (MR) after this treatment. Methods: Treatment consisted of fludarabine (25 mg/m2 IV) given on days 1–5, every 4 weeks, for 6 cycles; after the first cycle, oral fludarabine was allowed to be given orally at 40 mg/m2 with the same schedule. Molecular response (MR) was assessed by RT-PCR analysis of t(11;18) or by PCR assays for analysis of IgH gene rearrangements analyzing FR1, FR2 and FR3 in endoscopic biopsies. Results: Eight consecutive patients were included. Median age: 60 years (range: 45–77); 3 pts were in stage I, 2 stage II-1 and 3 stage IV according to Lugano system. Four out of 5 (80%) pts achieved a CR after three cycles and all eight cases (100%) achieved a CR after six cycles, for an overall response rate of 100%. After a median follow-up of 44 months (range 14.5–58 mo) no patient has shown clinical or endoscopic relapse. Hematological toxicity occurred in 75% of pts, mainly mild neutropenia and generally after the third cycle. Three cases received G-CSF (after the 2nd, 3rd and 6th cycle) and three patients required dose modification or delay (3–7 days) in the delivery of the following cycle. No blood transfusions were required. Only one patient had to be admitted because of non-neutropenic fever. None case of myelodisplasia has been detected at last follow-up. Four out of 8 pts (50%) achieved MR during the study-period (see figure). Four out of 5 (80%) pts without t(11;18) achieved MR. In contrast, no patient carrying t(11;18) achieved MR. Sequencing analysis of monoclonal PCR products will be presented. Conclusions: Fludarabine, either intravenous or oral, is safe and achieve a high response rate when given in gastric MALT lymphoma, with many pts achieving MR. In those pts carrying t(11;18), residual disease can be detected by PCR but do not determine relapse at present follow-up. Figure Figure

Recenti evidenze hanno dimostrato come la predisposizione rivesta un ruolo cruciale nel 5-10% dei tumori pediatrici. Ciò nonostante, è ancora un ambito nebuloso, che va ulteriormente investigato. Nell’adulto, l’evoluzione clonale agisce in modo simile: l’accumulo di mutazioni somatiche dovuto all’età, aumenta la prevalenza di neoplasie mieloidi tra gli individui più anziani. Come specifici pathway di co-occorrenza predispongano a tumori ematologici, è da indagare in modo più approfondito. In questo studio, ci siamo focalizzati sul ruolo della predisposizione genetica nei tumori ematologici del bambino e dell’adulto, allo scopo di migliorare le conoscenze riguardo alle alterazioni genetiche che agiscono nella fase pre-leucemica. Abbiamo realizzato il nostro studio attraverso diverse tasks, caratterizzate dall’obiettivo comune di scandagliare il ruolo della predisposizione genetica nel promuovere la trasformazione neoplastica. Innanzitutto, abbiamo sequenziato una corte di 120 diagnosi consecutive di pazienti pediatrici affetti da Leucemia Linfoblastica Acuta e casi sporadici con altri tumori ematologici, così come casi con ricorrenza familiare. Il profiling genetico ha confermato il ruolo cruciale di alcuni geni nella Leucemogenesi, come quelli appartenenti al pathway di RAS, sia in termini di incidenza, sia di patogenicità. Inoltre, ha fatto luce sulle mutazioni germinali nelle Coesine: queste alterazioni, solitamente associate a sindromi genetiche denominate Coesinopatie, non sono eventi sporadici, ma si presentano con una frequenza non trascurabile (6%) e degna di ulteriori approfondimenti. Considerando questa evidenza, ci siamo focalizzati sulle varianti germinali dei geni STAG1 e RAD21. I nostri risultati hanno dimostrato che queste alterazioni sono responsabili di una scarsa coesione cromatinica, promuovono quindi instabilità genetica spontanea e sono caratterizzati da meccanismi di riparo al danno del DNA difettivi. Pertanto, geni che non sono classicamente correlati alla fase conclamata delle neoplasie ematologiche pediatriche promuovono condizioni che predispongono al cancro, aggravando infatti il rischio di eventi somatici responsabili dell’insorgere della neoplasia. Al fine di valutare il contributo della predisposizione genetica considerando tutto l’arco della vita, abbiamo investigato il ruolo dell’Evoluzione Clonale nell’adulto. Nonostante sia considerato un fenomeno fisiologico nell’invecchiamento, è anche significativamente associato a malattie cardiovascolari, tumori solidi e neoplasie ematologiche. Lo screening mutazionale di 1794 individui anziani (oltre 80 anni) ha permesso di stabilire un modello basato su tre gruppi di rischio, in cui l’accumulo differenziale di mutazioni somatiche dipendente dall’età aumenta la prevalenza di neoplasie mieloidi o malattie associate all’infiammazione. Nello specifico, le mutazioni dei geni dello Splicing, di JAK2, o la presenza di mutazioni multiple (DNMT3A, TET2, ASXL1 con lesioni genetiche aggiuntive), nonché le varianti con frequenza allelica ≥ 0,096, hanno un valore predittivo positivo per le neoplasie mieloidi. Infine, abbiamo sottolineato il ruolo delle mutazioni dei geni dello Splicing non solo come eventi precoci nella patogenesi, ma anche in una fase precedente, figure chiave nel determinare l’insorgenza della malattia mielodisplasica. In conclusione, una migliore conoscenza e caratterizzazione di queste alterazioni può avere impatti clinici differenti. In primo luogo, può garantire una migliore comprensione del processo di tumorigenesi, aprendo nuovi scenari in merito al contributo della Predisposizione genetica e dell’Evoluzione Clonale nelle neoplasie ematologiche. Inoltre, può avere conseguenze significative sia nella terapia dei pazienti, sia nella consulenza genetica familiare: consentirebbe quindi strategie di sorveglianza mirate e aggiustamenti terapeutici paziente-specifici.
Despite genetic predisposition occurs in 5-10 % of pediatric cancer, it is still a nebulous field, that has to be better characterized. In the adult setting, clonal evolution acts similarly, and age-dependent accumulation of somatic mutations increases the prevalence of myeloid neoplasms among older individuals. How the specific co-occurrence of somatic events predisposes to hematological malignancies have to be further clarified. In the present project, we focused our attention in dissecting the role of genetic predisposition in both childhood and adult hematological malignancies, with the purpose of improving knowledge about genetic alterations that act in pre-leukemic phase. We planned and developed our study through several tasks, characterized by the joint purpose of investigating the contribution of genetic predisposition in promote tumor transformation. Firstly, we screened a cohort of 120 consecutive diagnosis of pediatric patients affected by Acute Lymphoblastic Leukemia and sporadic cases with other hematological malignancies, as well as cases with familiar recurrence. Genetic profiling confirmed the crucial role of some genes in Leukemogenesis, like those belonging to Ras pathway, both in term of incidence and pathogenicity. Moreover, it shed light on germline mutations in Cohesins: these alterations, usually associated to genetic syndromes called Cohesinopathies, are not random or sporadic events, but occur with a frequency (6%) that is not negligible and worthy of further study. Considering this evidence, we made a focus on STAG1 and RAD21 germline variants. Our results demonstrated that they lead to a poor chromosomal strength and promote spontaneous instability, resulting in a lowered response to exogenous and endogenous agents, as well as defective DNA repair mechanisms. So, genes that are not classically related to full-blown stage of hematological disease, promote cancer prone conditions in pediatric patients, aggravating the risk of somatic events that are responsible of the disease’ onset. In order to evaluate the contribution of genetic predisposition in cancer considering overall the time of life, we investigated the role of clonal evolution in the adult setting. Despite it is considered normal in aging, it is also significantly associated with cardiovascular disease, as well as solid tumors and hematological malignancies. The mutational screening of 1794 oldest-old individuals allowed to establish a model based on 3 risk groups, in which differential age-dependent accumulation of somatic mutations increases prevalence of myeloid malignancies or inflammatory-associated diseases. Specifically, mutations in Splicing genes, JAK2 or the presence of multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions), as well as variants with allele frequency ≥0.096, have a positive predictive value for myeloid neoplasms. Finally, we underlined the role of Splicing genes mutations not only as early events in pathogenesis, but also in a previous phase, as key players in determine the onset of myelodysplastic disease. Overall, a better knowledge and characterization of these alterations will have different impacts: it will improve the understanding of tumorigenesis, opening new scenarios regarding the contribution of genetic predisposition and clonal evolution to hematological malignancies. Moreover, it could have significative effects on both patients’ care and familial genetic counseling, enabling targeted surveillance strategies, and tailored therapeutical adjustments that include familiar screening in case of familiar donor in hematopoietic stem cell transplantation.

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Myelodysplastic Syndrome (MDS) is a group of clonal diseases of hematopoietic progenitor cells, characterized by peripheral cytopenia (s), dysplasia of one or more myeloid cell lines and increased risk of developing acute myeloid leukemia. SMD is considered a disease of the elderly, as approximately 80% of patients over 60 years are diagnosed with the disease. The causes of MDS are known in only 15% of cases. Regarding environmental factors as triggers of MDS, the use of prior chemotherapy, especially of alkylating agents and purine analogs and radiotherapy may be included. The pathogenesis of SMD involves DNA damage in hematopoietic stem cells, also resulting from single stranded DNA damage (SSB) in the DNA having three mechanisms: base excision repair (BER), base pair mismatch repair (MMR), and repair By nucleotide excision (NER), as repair processes necessary to ensure the genomic stability of stem cells. This cohort study aimed to evaluate the mRNA expression level of the single-stranded DNA repair mechanism, ERCC8 (CSA), ERCC6 (CSB) acting on the transcription-linked nucleotide excision repair mechanism (TC (XPG) and XPA acting at the confluence of the GG-NER and TC-NER subunits, associating the molecular findings with clinical variables (NER), XPC acting on the nucleotide excision repair mechanism linked to the global genome (GG-NER), ERCC5 And socio- demographic characteristics of patients with Myelodysplastic Syndrome. This analysis was based on the qPCR methodology, between bone marrow samples from 74 patients with MDS and 10 bone marrow samples from healthy elderly volunteers. Patients with MDS were diagnosed according to the criteria proposed by the World Health Organization and stratified according to the prognostic criteria established by the revised International Prognostic Score Index. With this study, it was possible to identify that: 1. patients diagnosed with hypocellular MDS presented increased levels of XPA and XPC gene expression and reduced ERCC8 (CSA) gene expression level; 2. Increased levels of ERCC8 (CSA), ERCC5 (XPG) and XPA gene were identified in poorer prognostic variables for MDS; 3. increased expression of the ERCC6 (CSB), ERCC5 (XPG) and XPA genes in cytopenic profiles representative of a more aggressive disease picture was observed; 4. MDS patients with increased ERCC8 (CSA) gene expression levels exhibited longer survival, and when increased expression levels of the ERCC5 (XPG), XPA and XPC genes exhibited lower survival; 5. In the analysis of correlations, the expression of the XPA gene showed a correlation of 26.8% with the expression of the ERCC5 gene (XPG), as well as, the expression of the XPA gene showed a 70.5% correlation with the expression of the XPC gene and, finally, XPC gene expression was found to have a 36.7% correlation with ERCC5 (XPG) gene expression.
A SÃndrome MielodisplÃsica (SMD) Ã um grupo de doenÃas clonais das cÃlulas progenitoras hematopoiÃticas, caracterizadas por citopenia(s) perifÃrica(s), displasia de uma ou mais linhagens celulares mielÃides e aumento do risco de desenvolvimento de leucemia mielÃide aguda. A SMD Ã considerada uma doenÃa de pessoas idosas, pois aproximadamente 80% dos pacientes acima de 60 anos sÃo diagnosticados com a doenÃa. As causas da SMD sÃo conhecidas em apenas 15% dos casos. Em relaÃÃo aos fatores ambientais como desencadeadores da SMD, podem ser incluÃdos o uso de quimioterapia prÃvia, especialmente de agentes alquilantes e anÃlogos da purina e radioterapia. A patogÃnese da SMD envolve danos no DNA nas cÃlulas tronco hematopoÃticas, oriundas tambÃm pelos danos de fita simples (SSB) no DNA tendo trÃs mecanismos: reparo por excisÃo de bases (BER), reparo de erros de emparelhamento de bases (MMR) e reparo por excisÃo de nucleotÃdeo (NER), como processos de reparo necessÃrios para garantir a estabilidade genÃmica das cÃlulas-tronco. Este estudo de coorte propÃs avaliar o nÃvel de expressÃo do mRNA dos genes atuantes no mecanismo de reparo em danos de fita simples no DNA, ERCC8 (CSA), ERCC6(CSB) atuantes no mecanismo de reparo de excisÃo de nucleotÃdeos ligado a transcriÃÃo (TC-NER), XPC atuante no mecanismo de reparo por excisÃo de nucleotpideos ligado ao genoma global (GG-NER), ERCC5(XPG) e XPA atuantes na confluÃncia das subvias GG-NER e TC-NER, associando os achados moleculares com variÃveis clÃnicas e sÃcio-demogrÃficas de pacientes portadores de SÃndrome MielodisplÃsica. Esta anÃlise baseou-se na metodologia de qPCR, entre amostras de medula Ãssea de 74 pacientes com SMD e 10 amostras de medula Ãssea de idosos voluntÃrios sadios. Os pacientes com SMD foram diagnosticados de acordo com os critÃrios propostos pela OrganizaÃÃo Mundial de SaÃde e estratificados de acordo com os critÃrios prognÃsticos estabelecidos pelo Ãndice de Escore PrognÃstico Internacional revisado. Com este estudo foi possÃvel identificar que: 1. pacientes diagnosticados com SMD hipocelular apresentaram aumento nos nÃveis de expressÃo dos genes XPA e XPC e reduzido nÃvel de expressÃo do gene ERCC8(CSA); 2. identificou-se que nÃveis de expressÃo aumentados do gene ERCC8(CSA), ERCC5(XPG) e XPA em variÃveis de pior prognÃstico para SMD; 3. foi observado um aumento de expressÃo dos genes ERCC6(CSB), ERCC5(XPG) e XPA em perfis de citopenias representativas de um quadro de doenÃa mais agressiva; 4. pacientes com SMD apresentando nÃveis de expressÃo aumentados do gene ERCC8(CSA) exibiram maior sobrevida e quando apresentando nÃveis de expressÃo aumentados dos genes ERCC5(XPG), XPA e XPC exibiram menor sobrevida; 5. nas anÃlises de correlaÃÃes verificou-se que a expressÃo do gene XPA apresentou correlaÃÃo de 26,8% com a expressÃo do gene ERCC5(XPG), bem como, a expressÃo do gene XPA exibiu correlaÃÃo 70,5% com a expressÃo do gene XPC e, por fim, foi verificado que a expressÃo do gene XPC exibiu correlaÃÃo de 36,7% com a expressÃo do gene ERCC5(XPG).

Myelodysplastic syndromes (MDS) are regarded as clonal disorders of haematopoietic stem cells (HSC). Recent evidence demonstrates that stromal microenvironment, in addition to HSC defects, plays a particular role via its direct contact with haematopoietic precursor cells (HPC). This thesis aims at evaluating the putative growth deficiencies of mesenchymal stromal cells (MSC) from MDS individuals compared with normal controls, exploring their adhesion profile, assessing the adhesion process-involved molecular substrates, and establishing correlations with their growth patterns and HPC dysfunctions. Functional assays revealed that MSC from MDS are intrinsically pathological, show a continuous decline of proliferation over a 14-day culture and a reduced clonogenic capacity in the absence of signals from HPC. MSC growth defects significantly correlate with decreased CD44 and CD49e expression. Moreover, stroma-dependent adhesion mechanisms control HPC clonogenic potential and CD49e might be one of the molecules involved in this process. Qualitative and quantitative abnormalities of focal adhesion (FA) proteins paxillin and pFAK [Y397] and of two regulatory proteins, HSP90αβ and p130CAS were identified via immunofluorescence analysis. Paxillin, pFAK [Y397] and HSP90αβ increased expression, besides its stronger nuclear colocalization in MSC from RAEB correlates with a consistent proliferative advantage and has a negative impact on HPC clonogenic capacity. These results open interesting opportunities, e.g. HPC-to-MSC interactions involve FA proteins signalling, and, as FAK is an HSP90αβ-client protein, it may enhance the utility of HSP90αβ inhibitors as adjuvant therapy in MDS