scholarly journals The emergence of a JAK2 V617F‐mutated clone in myelodysplastic syndrome is associated with disease progression and features of myelofibrosis

2019 ◽  
Author(s):  
Boris Zhong ◽  
L. Jeffrey Medeiros ◽  
Wei Wang
Keyword(s):  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Jak2 V617f

scholarly journals ASXL1 and STAG2 are Common Mutations in GATA2 Deficiency Patients with Bone Marrow Disease and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Robert R West ◽  
Katherine R Calvo ◽  
Lisa J Embree ◽  
Weixin Wang ◽  
Laura M Tuschong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Survival Probability ◽  
Somatic Mutations ◽  
Monosomy 7 ◽  
Myeloid Malignancies ◽  
Lower Survival ◽  
Common Diagnosis ◽  
Gata2 Deficiency

GATA2 Deficiency patients harbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 Deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic Syndrome (MDS) was the most common diagnosis (~44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID) (~37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between patient age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (~43%)- notably trisomy 8 (~23%) and monosomy 7 (~12%), but these changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ~25% of patients, though these mutations were rarely concomitant. Mutations in DNMT3A were found in ~10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 Deficiency

scholarly journals Acquisition of JAK2, PTPN11, and RAS mutations during disease progression in primary myelodysplastic syndrome

Leukemia ◽  
2006 ◽  
Vol 20 (6) ◽  
pp. 1155-1158 ◽  
Author(s):  
C-Y Chen ◽  
L-I Lin ◽  
J-L Tang ◽  
W Tsay ◽  
H-H Chang ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Ras Mutations

scholarly journals Expansion of myeloid derived suppressor cells correlates with number of T regulatory cells and disease progression in myelodysplastic syndrome

2015 ◽  
Vol 5 (2) ◽  
pp. e1062208 ◽  
Author(s):  
Astrid Olsnes Kittang ◽  
Shahram Kordasti ◽  
Kristoffer Evebø Sand ◽  
Benedetta Costantini ◽  
Anne Marijn Kramer ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
T Regulatory Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Regulatory Cells

scholarly journals The lack of association between JAK2 V617F mutation and myelodysplastic syndrome with or without myelofibrosis

Leukemia ◽  
2006 ◽  
Vol 20 (6) ◽  
pp. 1165-1165 ◽  
Author(s):  
S-F Yip ◽  
C-C So ◽  
Ay-Y Chan ◽  
Hs-Y Liu ◽  
Ts-K Wan ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
V617f Mutation

Flow Cytometric Detection of Human Telomerase Reverse Transcriptase Expression in CD34 Positive Precursor Fraction in Myelodysplastic Syndrome Bone Marrow.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4300-4300
Author(s):  
Hiroshi Handa ◽  
Takafumi Matsushima ◽  
Norifumi Tsukamoto ◽  
Masamitsu Karasawa ◽  
Hiroyuki Irisawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Risk Group ◽  
Telomerase Activity ◽  
Low Risk ◽  
Htert Expression ◽  
Trap Assay

Abstract Telomerase activity has been found in most common cancers indicating that telomerase detection may be a useful marker in cancer diagnosis. For detection of telomerase activity and the expression of associated genes in cells, TRAP assay and RT-PCR are customarily used. Immunohistochemical detection of hTERT is useful to detect telomerase-positive cells in a background of non- cancerous cells. We developed a method for the detection of intra-nuclear hTERT protein, in a sub-population of hematopoietic cells, using concurrent staining cell surface antigen and multi color flow cytometry. Human leukemia and myeloma cell lines showed 100% positivity, whereas neutrophils of normal subjects showed 0% positivity, it is consistent with telomerase activity assessed by TRAP assay (r=0.71, p<0.0001) and previous observations. Then we applied this method to analyze hTERT expression in myelodysplastic syndrome (MDS). Forty MDS patients samples were obtained, 36 patients were diagnosed as low risk MDS (RA), 14 patients were diagnosed as high risk MDS (RAEB or RAEB-t) according to FAB classification. All samples were acquired after informed consent was obtained from the patients. Expression of hTERT protein was higher in CD34-positive blast-gated cells than CD34-negative blast-gated cells. The percentage of the CD34+ cells expressing hTERT ranged from 9.66% to 90.91% in low risk MDS patients, whereas from 50.46% to 97.68% in high risk MDS. The expression level was higher in the high risk group compared to that in the low risk group in MDS (p=0.0054, p=0.0084). This observation implied that telomerase up-regulation and hTERT expression were important for disease progression and could be a marker of more advanced disease. In subsets of MDS and AML bone marrow specimens obtained from these patients, we examined the hTERT expression in CD34+/CD38 high cells and CD34+/CD38 low cells containing stem cell fraction. Of interest, some of the patients showed higher expression of hTERT in CD34+/CD38 low cells than in CD34+/CD38 high cells. This observation is inconsistent with previous reports describing normal bone marrow hematopoietic cell findings. We speculated that this phenomenon could be a marker of MDS abnormality and that telomerase up-regulation may be initiated in the more primitive precursor fraction containing hematopoietic stem cells during the disease progression. Telomerase studies may be useful for definition of the risks associated with disease severity. Multi-parameter nature of flow cytometry and its ability to identify cellular sub-populations will facilitate a fuller understanding of the mechanisms of activation of telomerase.

Leukocyte Alkaline Phosphatase Score as a Marker of Severity and Progression of Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4625-4625 ◽  
Author(s):  
Jay Lipshitz ◽  
Sewanti Limaye ◽  
Dilip Patel
Keyword(s):  
Bone Marrow ◽  
Alkaline Phosphatase ◽  
Myelodysplastic Syndrome ◽  
Disease Activity ◽  
Disease Progression ◽  
Myelogenous Leukemia ◽  
Bone Marrow Blast ◽  
Leukocyte Alkaline Phosphatase ◽  
Significant Difference ◽  
Bone Marrow Blasts

Abstract Leukocyte Alkaline Phosphatase (LAP) Score is valuable in the work-up of certain hematological diseases. Most notably, the score is decreased in Chronic Myelogenous Leukemia and Paraoxysmal Nocturnal Hemaglobinurea but increased in leukemoid reaction to infection and Polycythemia Vera. Last year we reported the LAP scores of 14 patients with Myelodysplastic Syndrome (MDS). Our results showed that patients with less than 5% bone marrow blasts had significantly higher LAP scores than patients with 5–19% bone marrow blasts. We raised the possibility that LAP scores decrease as MDS progresses (Blood, Nov 2006; 108: 4865). In the present study we attempt to further evaluate the utility of LAP in MDS. In addition to our original cohort, bone marrow aspirate results and LAP scores were reviewed from 14 more patients with MDS, for a total of 28 patients. We again assessed the relationship of LAP to bone marrow blast percentage. Furthermore, we recorded a second LAP score, taken at a later date, from 16 of the 28 patients. For those patients with two LAP scores we compared the trend of LAP score to the interval activity of MDS, using transfusion requirement, complete blood cell count (CBC) and clinical assessment as markers of disease activity. In our analysis of LAP score relative to bone marrow blast percentage we again found a significant difference between patients with less than 5% blasts (n=8) and those with 5% to19% blasts (n=20). Patients with less than 5% blasts had significantly higher LAP scores (90.25 ± 18.27) than those with 5 to19% blasts (44.35 ± 52.09) (p<0.0048) (see charts 1 and 2). In our analysis of LAP score in relation to disease progression we found that among patients for whom LAP score decreased, 42.9% (3/7) had disease progression. In patients whose LAP score increased, 11.1% (1/9) had disease progression (p<0.2615) (chart 3). Overall, our results confirm that LAP scores do tend to be lower in patients with more severe disease, as assessed by bone marrow blast percentage. However, although a trend was observed toward change in LAP score correlating with disease activity this was not statistically significant, and larger prospective studies are necessary to assess whether LAP is an accurate marker of MDS progression. Chart 1: LAP scores of patients 1 through 8 with bone marrow blasts less than 5% (mean 90.25, median 96) Chart 2: LAP scores for patients 1 through 20 with bone marrow blasts of 5% to 19% (mean 44.35, median 30) Chart 1: LAP scores of patients 1 through 8 with bone marrow blasts less than 5% (mean 90.25, median 96) . / Chart 2: LAP scores for patients 1 through 20 with bone marrow blasts of 5% to 19% (mean 44.35, median 30) Chart 3: Percent of patients with disease progression among those with decrease in LAP score (white) and those with increase in LAP score (gray) (p<0.2615). Chart 3: Percent of patients with disease progression among those with decrease in LAP score (white) and those with increase in LAP score (gray) (p<0.2615).

Update of a Phase I Study of Sorafenib in Patients with Refractory/Relapsed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 893-893 ◽  
Author(s):  
John Delmonte ◽  
Hagop M. Kantarjian ◽  
Michael Andreeff ◽  
Stefan Faderl ◽  
John J. Wright ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Maximal Response ◽  
Daily Dose ◽  
Grade 3 ◽  
Acute Myeloid

The critical importance of the Ras, VEGF, and FLT3 pathways in the pathogenesis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been well established. FLT3 abnormalities, internal tandem duplication (ITD) and point mutations, occur in about 30% of pts with AML and the FLT3-ITD mutation independently confers poor prognosis. Sorafenib is an oral multikinase inhibitor targeting the above pathways and is highly potent against FLT3-ITD mutants (IC50 1–3 nM) (ASH abstract, 2006). We are conducting a phase I trial to evaluate the safety and efficacy of two different schedules of sorafenib. To date, 21 patients (pts) with refractory/relapsed AML (n=20) and high risk MDS (n=1) have been enrolled. Pts were randomized to sorafenib for 5 days per week for 21 days (arm A; n=11) or for 14 days every 21 days (arm B; n=10). In both arms the starting dose level (DL) is 200 mg twice daily. Successive dose levels are 600, 800, and 1200 mg daily in a standard 3+3 design. Peripheral blood (PB) and bone marrow (BM) samples were obtained for evaluation of FLT3 status and phosphorylated and total FLT3 and ERK expression. Median age is 62 years (range, 33–82), number of prior therapies 2 (range, 1–5), time from diagnosis to sorafenib treatment 9 months (range, 2–46), and median duration on study was 1.2 months (range, 0.1–3.4). Twenty pts are evaluable. 9/20 (45%) pts received ≤ 1 cycle of sorafenib because of disease progression (n=6), self-discontinuation (n=2), or no benefit (n=1), of whom 5 (56%) were FLT3-ITD negative, 3 (33%) were FLT3-ITD positive, and 1 (11%) was not tested. In contrast, 11/20 (55%) pts received > 1 cycle of sorafenib, of whom 8 (73%) were FLT3-ITD positive and 3 (27%) were FLT3-ITD negative; reasons for discontinuation were disease progression (n=5), self-discontinuation (n=2), stem cell transplant (n=2), or no benefit (n=2). Sorafenib has been well tolerated with 1 pt achieving a DLT of grade 3 hyperbilirubinemia at the 800 mg daily dose in arm B, but the MTD has not been reached; this cohort has been expanded. The only other grade 3 toxicity has been pleural effusion at the 600 mg daily dose in arm A, not considered a DLT because it occurred during cycle 2. A ≥ 50% reduction in PB or BM blasts was obtained in 11/20 (55%) pts. 9/11 (82%) pts harbored the FLT3-ITD mutation and had a median duration of response of 42 days (range, 15–87). In these 9 pts, the median PB absolute blast count at baseline and after maximal response to sorafenib was 10.3 (range, 0.2–18.7) and 0 (range, 0–1)(p=0.008). Median BM blast percentage at baseline and after maximal response to sorafenib was 72% (range, 14–96) and 42% (range, 12–58) (p=0.002), with 1 pt achieving a morphologic complete remission in the BM. Serial determinations of phosphorylation status following sorafenib (at 0, 2, 24,120 hours) in pts with the FLT3-ITD mutation demonstrated inhibition of phospho-FLT3 in 3/3 and phospho-ERK in 5/5 pts. In conclusion, sorafenib administration is safe in AML and appears to preferentially target the FLT3-ITD mutation. This study continues to accrue pts to define the MTD and it will be followed by combination studies of standard chemotherapy with sorafenib, with an emphasis on targeting pts with AML expressing the FLT3-ITD mutation.

MDM2 SNP309 and TP53 SNPArg72Pro Polymorphisms in Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1745-1745
Author(s):  
João Agostinho Machado Neto ◽  
Fabiola Traina ◽  
Paula Melo Campos ◽  
Marilisia Andreoli ◽  
Irene Lorand Metze ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Low Risk ◽  
Healthy Controls ◽  
Mdm2 Snp309 ◽  
P53 Pathway ◽  
Hematopoietic Stem ◽  
High Risk Disease

Abstract Abstract 1745 Poster Board I-771 Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress towards acute myeloid leukemia (AML). The progression of the disease may be associated with genetic or epigenetic alterations and a possible change in protein function. MDM2/P53 pathway plays an important role in the control of apoptotic and proliferation mechanisms. Single nucleotide polymorphisms (SNPs) were identified in the TP53 and MDM2 genes. MDM2 SNP309 results in higher levels of MDM2 and attenuates p53 pathway. The SNP in codon 72 of the TP53 gene results in either a C or G nucleotide and leads to either Proline (Pro) or Arginine (Arg), respectively. The Arg variant has been shown to be more potent in apoptosis induction and the Pro variant has been shown to be better in inducing cell-cycle arrest and to have a greater ability to repair damaged-DNA. The aim of the present study was to investigate the incidence of MDM2 and TP53 polymorphisms in MDS patients and to correlate the frequency of these SNPs with age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB (RA and RARS versus AREB and AREBt) and IPSS (Low and Int-1 versus Int-2 and high), cytogenetic risk (low versus intermediate and high risk), disease progression and overall survival. Patients and Methods We studied 103 healthy controls and 63 patients with MDS. According to FAB, patients were distributed as follows: 43 RA, 10 RARS, 7 RAEB, 1 RAEBt and 2 CMML. The median follow-up time was 40 months (range 2 – 159 months). Samples were obtained from peripheral blood or bone marrow and were screened for the presence of polymorphisms MDM2 SNP309 and TP53 SNPArg72Pro, by PCR analysis with specific primers and appropriate restriction enzyme. Appropriate statistical analyses were used for each test. Results The frequencies of genotypes for MDM2 SNP309 and TP53Pro7Arg were similar between MDS and healthy controls; MDM2 SNP309: 51% vs 53%, for TT, 38% vs 32% for TG, and 11% vs 15% for GG, TP53Pro7Arg: 47.5% vs 44%, for Arg/Arg, 47,5% vs 42% for Pro/Arg, and 5% vs 14% for Pro/Pro. No differences were observed between MDS patients with presence or absence of the polymorphisms in relation to age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB, IPSS and cytogenetic risk, disease progression and overall survival. Conclusions MDM2 and TP53 polymorphisms have been described to affect the risk for cancer, onset age and overall survival in solid tumors and leukemias. This was the first study to report these SNPs in MDS and leads to believe that these polymorphisms are not associated with risk for the disease and with clinical data. Keywords: MDM2, p53, myelodysplasia, polymorphisms Disclosures No relevant conflicts of interest to declare.

Outcomes of Patients with Myelodysplastic Syndromes/Myeloproliferative Neoplasms with Emphasis On MDS/MPN-Unclassified

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5025-5025
Author(s):  
Charikleia Kelaidi ◽  
Varnavas Constantinou ◽  
George Papaioannou ◽  
Niki Stavroyianni ◽  
Chrysanthi Vadikoliou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Jak2 V617f ◽  
Female Ratio ◽  
Wbc Count

Abstract Abstract 5025 Background: Data on outcomes of patients (pts) with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), especially MDS/MPN-unclassified (MDS/MPN-U), are scarce. Patients/methods: We retrospectively studied pts followed in our center, with MDS/MPN according to WHO 2008 criteria. Because of overlap characteristics of MPN and MDS, pts with systemic mastocytosis associated with MDS (SM/MDS) were also included. Pts with previous MDS or MPN were excluded. Response and disease progression were defined according to IWG 2006 criteria. Results: Twenty-five pts with MDS/MPN were included. Median age was 70 y (range 19–79). Male/female ratio was 1.77/1. Diagnosis was CMML-1 N=7, CMML-2 N=7, JMML N=1, MDS/MPN-U N=8, systemic mastocytosis (SM)/MDS N=2, with one additional pt with CMML subsequently developing SM. At diagnosis, median WBC count was 18.8 G/L (range 3–120), ANC 15.5 G/L (0.6–70), monocytes 1.9 G/L (0.1–16), left shift 16% (0–28), Hb 11.2 g/dL (6–17), platelets 99 G/L (10–680), peripheral and bone marrow (BM) blasts 5% (0–17) and 7% (2–19), respectively (resp.). 25% of pts had platelets count ≥400 G/L. Splenomegaly, B-symptoms and BM fibrosis were present in 23%, 57% and 27% of pts, resp. Karyotype was fav, int and unfav in 55%, 36% and 9% of pts, with −7, +8, del(12)(p11), del(12)(q14;q21), +10, +21, and previously unreported t(9;12)(q13;q13) in 3, 6, and 1 pt each, resp., while +21 and i(17)(q10) appeared during disease progression other than AML transformation. IPSS was low/int-1 and int-2/high in 50% and 50% of pts, resp. JAK2 V617F and CKIT D816V mutations were detected in 2/6 pts and 2/2 SM/MDS pts, resp. 70% and 29% of pts were transfused at diagnosis with PRBC and platelets, resp. Treatment included erythropoiesis stimulating agents (ESAs), low dose chemotherapy, intensive chemotherapy (IC) and azacitidine (AZA) in 40%, 36%, 16% and 48% of pts resp. Response rate to ESAs, IC and AZA was 60%, 14% and 14% resp. Response rate to AZA in CMML-1 pts was 33%. Dasatinib yielded no response in 1 SM/MDS pt with CKIT D816V. 3-year cumulative incidence of AML and median overall survival (OS) in pts with CMML-1, CMML-2 and MDS/MPN-U were 20%, 40% and 0 (P=0.059) and 39, 8, and 20 mo (P=0.50), resp. The pt with JMML died from AML transformation 3 months after diagnosis. 2/3 pts with SM/MDS died from disease progression w/o AML at a median of 10 mo after diagnosis. Median survival after disease progression other than AML transformation was 35, 15 and 14 mo in pts with CMML-1, CMML-2 and MDS/MPN-U, resp. (P=0.88). Cause of death was disease progression other than AML, AML transformation and unrelated to disease in 50%, 50%, and 0 and 80%, 0 and 20% of cases in CMML and MDS/MPN-U, resp. (P=0.10). Percentage of circulating blasts ≥5% was the only independent factor affecting risk of AML transformation in the overall population (P=0.0004). Diagnosis other than CMML-1, WBC ≥30 G/L, % of circulating blasts ≥5% and IPSS high/int-2 were associated with worse survival in univariate analysis (P=0.06, 0.03, 0.04 and 0.08, resp.). No predictive factor of OS was found in multivariate analysis. Conclusion: MDS/MPN are heterogeneous disorders with respect to disease progression and AML transformation. MDS/MPN-U tended to differ from CMML-1 by shorter survival after disease progression other than AML, and from CMML-2 by lower risk of AML transformation. Mortality of pts with MDS/MPN-U was mainly attributed to disease progression without AML transformation. Alternatively to hypomethylating agents, therapeutic options in pts with MDS/MPN-U could include JAK2 inhibitors. Disclosures: No relevant conflicts of interest to declare.

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