The Role Of Mutations On Genes RPS14, MIR145, MIR146A, In Myelodysplastic Syndrome

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Prognostic Value of Serum Ferritin, Transferrin Saturation and C- Reactive Protein At Diagnosis In Myelodysplastic Syndrome Patients: Analysis of Patients From the MDS Piedmont Registry,

Blood ◽

10.1182/blood.v118.21.3807.3807 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3807-3807 ◽

Cited By ~ 1

Author(s):

Emanuela Messa ◽

Daniela Gioia ◽

Claudia Bertassello ◽

Gianni Ciccone ◽

Andrea Evangelista ◽

...

Keyword(s):

Oxidative Stress ◽

Myelodysplastic Syndrome ◽

Negative Impact ◽

Transferrin Saturation ◽

C Reactive Protein ◽

Prognostic Role ◽

Normal Range ◽

Reactive Protein ◽

Iron Parameters

Abstract Abstract 3807 Background: The prognostic role of serum ferritin (SF) evaluation at baseline in patients (pts) affected by myelodysplastic syndrome (MDS) is still controversial. In fact, increased SF mainly due to transfusion requirement during disease history has a clear negative impact on overall survival (OS) (Malcovati et al., 2006) and also on leukemic evolution (LE) (Sanz, ASH 2008, de Swart ASH 2010) while contrasting data about its role at baseline on OS has been published. Park and colleagues (ASH 2010) failed to identify a negative prognostic impact of SF higher than 300 ng/mL in a cohort of low risk untransfused MDS patients while data from the European LeukemiaNet MDS registry identified SF as an independent prognostic factor for OS and progression-free survival in low- and int-1 MDS (de Swart, Edimburgh 2011). SF can be a marker of iron overload but also of inflammation and little is known about the impact on survival of other iron parameters such as transferrin saturation (TS) or inflammation such as C reactive protein (CRP) in MDS pts at diagnosis. Aim: Aim of our study was to evaluate the prognostic role of iron parameters and inflammation at diagnosis in MDS patients analyzing data collected in the MDS Piedmont Registry. Materials and methods: 1360 patients enrolled in the MDS Piedmont Registry (1999–2010) were analyzed. Patients with information on OS and LE and available baseline SF (n=670), TS (n=299), CRP (n=287) were included in the analysis. Survival analysis was performed using Kaplan-Meier method. Patients were stratified according to a cut off value of 800 ng/mL for SF, 40% for TS and values within or higher the normal range (0,8 mg/dL) for CRP. In order to compare survival curves, log-rank test was used. Cumulative incidence of LE, according to SF, TS and CRP levels, was calculated accounting for death from any causes as a competing event. Results: In the population with SF baseline values, 3-years OS in pts with SF < 800 ng/mL was 80.7 (95%CI: 75.8–84.8) and in pts with SF >800 ng/mL was 66.1 (95%CI: 46.7–79.8) (p= 0,006). The result seems to be confirmed in the low risk MDS subgroup in toto (n=226) and considering only the untransfused pts (136 cases) (p=0,0073 and p=0,0038 respectively) but no statistically significance in OS of high risk pts (n=108) has been observed. In subjects with available data on TS, 3-years OS for pts with TS lower than 40% was 75.0 (95% CI: 64.2–83.0) while in pts higher than 40% was 72.1 (95%CI: 59.5–81.4) (p=0,1). Finally, in pts with CRP values 3-years OS was 80.8 (95%CI: 69.7–88.2) for patients < 0,8 mg/dL and 47.2 (95%CI: 34.5–58.9) for pts > 0,8 mg/dL. Also 3-year cumulative incidence of LE was higher in pts with SF > 800 ng/mL [35.8 (95%CI: 20.3–51.2) vs 18.5 (95%CI: 14.4–22.5); p=0,002 ] and in those with CPR > 0,8 mg/dL [35.3 (95%CI: 23.9–46.7) vs 12.7 (95%CI: 5.7–19.7); p<0,001]. In TS subgroups no difference was observed [13.5 (95%CI: 7.0–20.0) for TS<40% vs 20.8 (95%CI: 11.8–29.8) for TS>40%; p=0.172]. Conclusions: although the limits of missing data, our results suggest that high levels of SF and CRP above the normal range at baseline should have a prognostic role in MDS pts, while TS seems to have little impact on OS. Moreover SF and CRP seem to have both a negative impact on LE. Our data suggest a more important prognostic role of chronic inflammation parameters than iron overload or oxidative stress in MDS patients at diagnosis. Further prospective evaluation of more specific parameter of oxidative stress and inflammation need to be analyzed in order to confirm our preliminary observation. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Intravenous Immunoglobulin Is an Effective Treatment for LGL-Mediated Immune Cytopenias in Myelodysplastic Syndromes and Other Bone Marrow Failure Syndromes

Blood ◽

10.1182/blood.v126.23.1704.1704 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1704-1704

Author(s):

Francesca Schieppati ◽

Erin P. Demakos ◽

Odchimar Rosalie-Reissig ◽

Shyamala C. Navada ◽

Lewis R. Silverman

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Aplastic Anemia ◽

Intravenous Immunoglobulin ◽

Hemolytic Anemia ◽

Bone Marrow Failure ◽

Myeloproliferative Neoplasm ◽

Recurrent Fever

Abstract Background: Myelodysplastic Syndrome (MDS) and Aplastic Anemia (AA) are often associated with clinical immune manifestations. An abnormal profile of the T-cell repertoire can be detected in these patients (pts) and is thought to play a role in bone marrow (BM) insufficiency. The presence of a co-existent large granular lymphocytic (LGL) clone may exacerbate cytopenias independent of the primary disease mechanism and offers another target for therapeutic intervention. Treatment for LGL proliferation is usually immunosuppressive therapy but there is no accepted standard of care. Methods: We explored the role of intravenous immunoglobulin (IVIG) as a treatment for immune-related cytopenias, i.e. Coombs negative (C-) hemolytic anemia, in a series of 12 consecutive pts with an LGL clonal proliferation documented by flow cytometry and TCR clonal rearrangements. Of the 12 cases, 9 had MDS (7 lower-risk), 1 AA with LGL liver involvement, and 1 primary myelofibrosis. One patient (pt) had suspected MDS. Overall response was assessed by MDS IWG criteria 2006. We defined a hemolysis response (HLR) as complete normalization (CR) or, a greater than 50% improvement (PR) in deviation from normal values of LDH, reticulocytes, indirect bilirubin and haptoglobin. Duration of HLR was defined as the time from onset of HLR to the time of resumption of hemolysis and loss of effect of IVIG. Results: All pts were treated with IVIG administered at a dose of 500mg/kg of IVIG once per week, in repeated cycles, with a duration ranging from 1-4 week(s) per cycle. Clinical characteristics (Table 1): M/F ratio 10/2; median age 69. Ten pts had a CD3+ T-LGL and 2 had a CD3-/CD16+/CD56+ NK-LGL circulating clone. Karyotype abnormalities were non-specific; 8 pts had 1-3+ reticulin BM fibrosis; 4 had mutations in RNA-splicing genes: SF3B1 (2); SETBP1 (1); SRSF2 (1). Ten pts were evaluable for response: 8 pts responded (ORR 80%): Hematological improvement (HI-erythroid) 8/8 (100%); a hemolysis CR (HLR-CR) occurred in 7 (87.5%) and hemolysis PR (HLR-PR) in 1 pt (12.5%). Median number of cycles, follow up, and duration of treatment were 16, 21.5 and 9.5 months (mo), respectively. The HLR-CR was durable and prolonged in 3/8 (38%) pts; 2 of these 3 pts (67%) did not require maintenance IVIG. Relapse from HLR occurred in 4, during infection or chemotherapy, but the response returned to the original level by shortening the intervals between administration of IVIG. One pt had relapsed after an initial response and then became refractory to IVIG. In follow up at month 38, 75% of pts were still responding to treatment, and 1 pt was still in remission after 46 mo. In 4 of 6 pts, corticosteroid treatment was discontinued and no longer required for chronic hemolysis, with general improvement of steroid related symptoms. Some patients had been on steroids maintenance for periods ranging from months to years. Response was more durable with continuous rather than sporadic dosing. Adverse events were not specific: 1 pt with self-limited isolated palpitations; 1 pt with hypertension not requiring intervention. Conclusions: Treatment with IVIG of immune cytopenias associated with LGL clones and BMF yields durable responses in 80% of pts. IVIG, especially at high concentrations, may enhance apoptosis, suppress proliferation of T-cells and induce immune-regulation. Given the relative rarity of LGL clones in MDS, further investigational studies will help define the role of IVIG and clarify the mechanism of action in this group of pts with MDS and BMF associated with LGL clones. Table 1. Variable Observed % Symptomatic anemia (fatigue, SOB) 9/12 75 B symptoms (recurrent fever) 2/12 16.6 Infections (bacteremia Campylobacter with migratory arthritis and dermatitis; cellulitis bacteremia S. epidermidis and osteomyelitis) 2/12 16.6 Skin lesions (leg focal ulceration and dermal fibrosis) 1/12 8.3 Splenomegaly 7/12 58.3 Hepatomegaly 2/12 16.6 Adenopathy (mediastinal) 1/12 8.3 Neuropathy 2/12 16.6 Hematologic disorders 11/12 91.6 Myelodysplastic syndrome 9/12 75 Severe aplastic anemia 1/12 8.3 Myeloproliferative neoplasm (PMF) 1/12 8.3 Lymphoproliferative neoplasm (FL+MDS) 1/12 8.3 Hemolytic anemia 11/12 91.6 Solid tumors (anal, squamous cell; breast ca) 2/12 16.6 Autoimmune disorders 7/12 58.3 ITP 3/7 42.8 Ulcerative colitis 1/7 14.3 Pernicious anemia 1/7 14.3 Systemic lupus erythematosus 1/7 14.3 Immune pancreatitis 1/7 14.3 MGUS 4/12 33.3 Disclosures Off Label Use: IVIG.

Download Full-text