scholarly journals BCL2L10 positive cells in bone marrow are an independent prognostic factor of azacitidine outcome in myelodysplastic syndrome and acute myeloid leukemia

Oncotarget ◽  
2017 ◽  
Vol 8 (29) ◽  
pp. 47103-47109 ◽  
Author(s):  
Valérie Vidal ◽  
Guillaume Robert ◽  
Laure Goursaud ◽  
Laetitia Durand ◽  
Clemence Ginet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Independent Prognostic Factor ◽  
Acute Myeloid

Analysis of Concerted Expression of Angiogenic Growth Factors in Acute Myeloid Leukemia: Expression of Angiopoietin-2 Represents an Independent Prognostic Factor for Overall Survival

2005 ◽  
Vol 23 (6) ◽  
pp. 1109-1117 ◽  
Author(s):  
Sonja Loges ◽  
Gerhard Heil ◽  
Melanie Bruweleit ◽  
Volker Schoder ◽  
Martin Butzal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Independent Prognostic Factor ◽  
Prognostic Impact ◽  
Angiogenic Growth Factors ◽  
Angiopoietin 2 ◽  
Acute Myeloid

Purpose Bone marrow neoangiogenesis plays an important pathogenetic and possible prognostic role in acute myeloid leukemia (AML). Members of the vascular endothelial growth factor (VEGF) and angiopoietin family represent the most specific inducers of angiogenesis secreted by AML blasts. We therefore correlated expression of angiogenic factors with clinical variables. Patients and Methods We investigated the expression of VEGF-A, VEGF-C, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), and the receptor Tie2 by quantitative polymerase chain reaction in a cohort of 90 patients younger than 61 years with de novo AML entered into the German AML Süddeutsche Hämoblastose Gruppe Hannover 95 trial. Uni- and multivariate analyses were performed using clinical and gene expression variables. Results Univariate analysis of overall survival indicated the following variables as prognostic factors: good response on a day-15 bone marrow examination after initiation of induction chemotherapy, karyotype, and high Ang2 expression. In multivariate analysis, only bad response and log Ang2 expression remained of statistical significance, with a hazard ratio of 3.51 (95% CI, 1.91 to 6.47) and 0.75 (95% CI, 0.61 to 0.91), respectively. Subgroup analysis suggested that the prognostic impact of Ang2 expression was especially evident in cohorts with low VEGF-C and Ang1 mRNA levels. Conclusion These results show that expression of Ang2 represents an independent prognostic factor in AML. Additional research into interactions of angiogenic cytokines in the pathogenesis of bone marrow angiogenesis in AML is warranted.

NUP98-HOXD13 Transgenic Mice Develop Myelodysplastic Syndrome, Acute Myeloid Leukemia, and Pre-T Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 345-345
Author(s):  
Yingwei Lin ◽  
Christopher Slape ◽  
Zhenhua Zhang ◽  
Peter D. Aplan
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Transgenic Mice ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Gene Rearrangements ◽  
Hematologic Disease ◽  
Amino Terminal ◽  
Acute Myeloid

Abstract The NUP98 gene is located at chromosome 11p15 and encodes the 98 kd component of the nuclear pore complex; this protein normally functions as a docking protein involved in nucleocytoplasmic transport. NUP98 is fused to at least 15 different partner genes by chromosomal translocation in a wide spectrum of hematological malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and pre-T lymphoblastic leukemia (pre-T LBL). Over half of the known NUP98 gene fusions involve fusions to a HOX family member; these fusions invariably retain the amino terminal FG repeats of NUP98 and the homeodomain DNA-binding region of the HOX partner. The NUP98-HOXD13 fusion was initially identified in a patient with MDS that subsequently transformed to erythroleukemia, and has subsequently been identified in AML M1 and M2 patients as well. To model this disease in vivo, we generated transgenic mice which expressed the NUP98-HOXD13 (NHD13) fusion from vav regulatory elements. The NHD13 transgene is ubiquitously expressed in hematopoietic tissues such as thymus, spleen, and bone marrow, and is not expressed in other tissues. Serial CBCs from clinically healthy mice aged 4–7 months demonstrated a progressive neutropenia, lymphopenia, anemia, and macrocytosis. Peripheral blood smears showed signs of dysplasia including giant platelets and hypersegmented neutrophils; bone marrow exam showed an increase number of dysplastic binucleate erythroblasts and increased apoptosis, consistent with a diagnosis of MDS. 10/10 (100%) of the NHD13 mice died of hematologic disease by 14 months of age; in contrast, none of the non-transgenic control littermates developed evidence of hematologic disease. We classified the hematologic diseases according to the Bethesda proposals. Three mice died with MDS, two mice had pre-T LBL, two had acute undifferentiated leukemia, one had megakaryocytic leukemia, one had myeloid leukemia with maturation, and one had both pre-T LBL and erythroid leukemia. The malignant blasts from mice with pre-T LBL showed monoclonal T-cell receptor B gene rearrangements and were positive for CD3, 4, and 8. The mouse with megakaryocytic leukemia had serial CBCs documenting a platelet count of 3.2 million/uL, rising to >15million/uL at the time of death. This mouse had CD41+ megakaryocytes and megakaryoblasts invading the liver and spleen, and an osteosclerotic bone marrow reminiscent of chronic idiopathic myelofibrosis (CIMF). The mouse with concurrent pre-T LBL and erythroid leukemia had replacement of the thymus and infiltration of the lung with T-lymphoblasts which had a clonal TCRB gene rearrangement; interestingly, the spleen, liver, and bone marrow of this mouse were invaded with erythroblasts that were negative for CD3 and TCRB gene rearrangements. We conclude that the NHD13 transgene consistently induces an MDS, of variable severity, in these mice. Some mice die of severe anemia due to MDS, and MDS transforms into an acute non-lymphoid leukemia in other mice. Still other mice die of pre-T LBL which we believe evolves in the thymus separately from the MDS. These data demonstrate that the NHD13 fusion gene is transforming in both lymphoid and myeloid cells.

Flt3 Receptor Inhibition Abolishes Constitutive NFκB Activation in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2434-2434
Author(s):  
Jennifer Grosjean ◽  
Lionel Ades ◽  
Simone Bohrer ◽  
Pierre Fenaux ◽  
Guido Kroemer
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Plasma Membrane ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Constitutive Activation ◽  
Nf Kappab ◽  
Acute Myeloid

Abstract High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NF-kappaB, via the activation of the IKK complex. We show that constitutive activation of the receptor tyrosine kinase Flt3 is responsible for IKK activation and this activation of the NF-kappaB pathway was found to involve a not yet described phosphorylation of the IKK and IkBa complex involving tyrosine residues compared to serine residues in the classical NF-kappaB pathway. Chemical inhibition or knockdown of Flt3 with small interfering RNAs abolished NF-kappaB activation in MDS and AML cell lines, as well as in primary CD34+ bone marrow cells from patients, causing mitochondrial apoptosis. Epistatic analysis involving the simultaneous inhibition of Flt3 and IKK indicated that both kinases act via the same anti-apoptotic pathway. An IKK2 mutant with a constitutive kinase activity and a plasma membrane-tethered mutant of NEMO that activates IKK1/2 prevented the cytocidal action of Flt3 inhibition. IKK2 and Flt3 physically associated in MDS and AML cells and Flt3 inhibition caused the release of IKK2 from a preferential association with the plasma membrane. Flt3 inhibition only killed CD34+ bone marrow cells from high-risk MDS and AML patients, in correlation with the blast numbers and the NF-kappaB activity, yet had no lethal effect on healthy CD34+ cells or cells from low-risk MDS. These results suggest that Flt3 inhibitors might exert an anti-neoplastic effect in high-risk MDS and AML through inhibition of constitutive NF kappaB activation.

EVI1 Overexpression in Pediatric Acute Myeloid Leukemia Associated with Unfavorable Subtypes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1802-1802
Author(s):  
Brian V Balgobind ◽  
Sanne Lugthart ◽  
Iris H.I.M. Hollink ◽  
Susan T.J.C.M. Arentsen-Peters ◽  
Elisabeth R van Wering ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Independent Prognostic Factor ◽  
Older Children ◽  
Microarray Gene Expression ◽  
Treatment Protocols ◽  
Monosomy 7 ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract The EVI1 (ecotropic virus integration-1) gene plays an important role in hematopoiesis especially in megakaryocyte development. The MDS1 gene is located upstream of EVI1, and its function is currently unknown. Normally the MDS1/EVI1 intergenic splice variant is co-expressed with EVI1. In adult acute myeloid leukemia (AML) overexpression of EVI1 (EVI1+) can be found in patients with chromosome 3q26-rearrangements. Often, these patients do not co-express MDS1/EVI1. Recently high EVI1 expression was also discovered in a separate subgroup of patients that did not have 3q26-rearrangements. Occasionally, they did not show overexpression of MDS1/EVI1. In these patients cryptic inversions of chromosome 3 were identified with fluorescence in situ hybridization (FISH). Of interest, EVI1+ was found to be an independent poor prognostic marker in adult AML (Lugthart et al, Blood 2008). In pediatric AML, 3q26-rearrangements are rare and the role of EVI1 is unknown. In this study, we investigated the frequency and clinical relevance of EVI1+ in pediatric AML. EVI1 expression was analyzed in 233 pediatric AML patients, of whom microarray gene expression profiling data were available. EVI1+ was found in 25 pediatric AML patients (11%), and confirmed with real-time quantitative PCR. This included 13/49 (26%) patients with MLL-rearranged AML: 5/22 (23%) cases with t(9;11); and all (n=4) cases with t(6;11). Moreover, EVI1+ was found in 4/7 (57%) cases with AML M7; in 2/3 (66%) cases with AML M6; in both cases with monosomy 7; in 1/43 (2%) cases with normal cytogenetics; in 2 patients with random cytogenetics, and in 1 patient with a cytogenetic failure. EVI1+ was not found in the t(8;21), inv(16) and t(15;17) subgroups. 3/25 EVI1+ patients lacked the MDS/EVI1 transcript, but no cryptic 3q26-rearrangements were detected with FISH. Molecular analysis showed that one patient had a CEBPα mutation; one patient had an FLT3-ITD; and 3 patients showed a mutation in the RAS oncogene. EVI+ was not correlated with sex or white blood cell count. However, the frequency in children younger than 10 years old was twice as high when compared to older children (14% vs 7%, p=0.12). Survival analysis was restricted to the subset of patients who were treated using uniform DCOG and BFM treatment protocols (n=204). In this cohort, EVI1+ patients had a worse 5-years event-free survival (pEFS) compared to patients without EVI1+ (30 vs. 43%, p=0.02). However, multivariate analysis, including cytogenetics (favorable [t(8;21, inv(16), t(15;17)] vs. other), FLT3-ITD, age and WBC, showed that EVI1+ was not an independent prognostic factor for survival. Moreover, within the unfavorable/normal cytogenetic subgroup, there was no difference in outcome between patients with and without EVI1+. We conclude that EVI1+ is found in ~10% of pediatric AML, and highly correlated with specific unfavorable cytogenetic (MLL-rearrangements) and morphologic (FAB M6/7) subtypes. In contrast to adult AML, no 3q26-rearrangements or cryptic inversions were found, and EVI1+ was not an independent prognostic factor. This difference in prognostic relevance may be due to differences in treatment. Alternatively, these results may indicate that EVI1 plays a different role in disease biology between adult and pediatric AML. This is at least suggested by the lack of 3q26 aberrations in pediatric AML.

scholarly journals Acute Myeloid Leukemia with Basophilic Differentiation Transformed from Myelodysplastic Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yasuhiro Tanaka ◽  
Atsushi Tanaka ◽  
Akiko Hashimoto ◽  
Kumiko Hayashi ◽  
Isaku Shinzato
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Bone Marrow Failure ◽  
Immunosuppressive Treatment ◽  
Flow Cytometric Analysis ◽  
Chromosomal Analysis ◽  
Monosomy 7 ◽  
Acute Myeloid

Myelodysplastic syndrome (MDS) terminally transforms to acute myeloid leukemia (AML) or bone marrow failure syndrome, but acute myeloid leukemia with basophilic differentiation has been rarely reported. An 81-year-old man was referred to our department for further examination of intermittent fever and normocytic anemia during immunosuppressive treatment. Chromosomal analysis showed additional abnormalities involving chromosome 7. He was diagnosed as having MDS. At the time of diagnosis, basophils had not proliferated in the bone marrow. However, his anemia and thrombocytopenia rapidly worsened with the appearance of peripheral basophilia three months later. He was diagnosed as having AML with basophilic differentiation transformed from MDS. At that time, monosomy 7 was detected by chromosomal analysis. We found that basophils can be confirmed on the basis of the positivity for CD203c and CD294 by flow cytometric analysis. We also found by cytogenetic analysis that basophils were derived from myeloblasts. He refused any chemotherapy and became transfusion-dependent. He died nine months after the transformation. We should keep in mind that MDS could transform to AML with basophilic differentiation when peripheral basophilia in addition to myeloblasts develops in patients with MDS.

scholarly journals Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3616-3616 ◽  
Author(s):  
Yanqin Yang ◽  
Yubo Zhang ◽  
Jun Zhu ◽  
Catherine E. Lai ◽  
Jingrong Tang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Nras Mutation ◽  
Trisomy 8 ◽  
Acute Myeloid

Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document