Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1866-1868 ◽  
Author(s):  
Hesham M. Amin ◽  
Iman Jilani ◽  
Elihu H. Estey ◽  
Michael J. Keating ◽  
Amanda L. Dey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
B Lymphocytes ◽  
Myeloid Leukemia ◽  
Immune Modulation ◽  
Refractory Anemia ◽  
Healthy Controls ◽  
Microenvironmental Factors ◽  
Acute Myeloid

AbstractThe hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of MDS.

Comparative Single Institute Analysis of Cord Blood Transplantation From Unrelated Donors with Unrelated Bone Marrow or Related Peripheral Blood Stem-Cell Transplants in Adult Patients with Acute Myeloid Leukemia / Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3382-3382
Author(s):  
Kazuhiro Masuoka ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
Hisashi Yamamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract Abstract 3382 Poster Board III-270 Recently, unrelated cord blood transplant (UCBT) has been widely applied to those who lack available related or unrelated donors. However, some results in those reports were conflicting, especially for transplantation-related mortality (TRM). The US study demonstrated a poor outcome for TRM in CBT recipients compared with human leukocyte antigen (HLA)–matched bone marrow transplant (BMT) recipients (NEJM. 2004; 351:2265). On the other hand, Takahashi et al showed excellent outcome (TRM 9% and disease free survival, DFS 70%) in CBT (Blood. 2007; 109:1322). Since there has been not much data available regarding this issue, we retrospectively extracted to adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS) and analyzed retrospectively the results of 245 recipients who underwent allogeneic stem cell transplantation (allo-SCT). We reviewed medical records of 290 patients with AML/MDS who had received allo-SCT from an unrelated donor between June 2000 and March 2009 at our institute, Tokyo, Japan. Since patients who had previous hematopoietic stem cell transplantations, active serious infection and performance status > 2, were excluded, 45 were subjected to the following analysis. Finally, the study includes 245 recipients of UCB (n = 140), UBM (n = 63), and related mobilized peripheral blood (RPB, n = 42) for de novo AML (n = 132), MDS overt AML (n = 79), refractory anemia (RA, n = 15), and refractory anemia with excess of blasts (RAEB, n = 19). Patient s median age for UCB, UBM, and RPB recipients were 59 (17 - 72), 55 (23 – 70), and 55 (22 – 67), respectively. UCB recipients had more serologically HLA-mismatched grafts (97% vs. 38% vs. 22%, P < .01), were conditioned more frequently with melphalan (75% vs. 27% vs. 20%, P < .01) and with total body irradiation (86% vs. 80% vs. 12%, P < .01 and used more tacrolimus (78% vs. 81% vs. 15%, P < .01) and less methotrexate (0% vs. 98% vs. 85%, P < .01) for graft-versus-host disease (GVHD) prophylaxis. Disease status consisted of standard (CR1 or CR2 of AML and RA, n = 62) and advanced groups(other status, n = 183). UCB recipients had significantly advanced status relative to UBM and RPB recipients (84% vs. 57% vs. 69%, P < .01) at the time of transplantation. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 787 days (119 – 2314), 1050 days (244 – 3059), and 1287 days (141 – 3004) for UCB, UBM, and RPB recipients, respectively. The incidence of grade II–IV acute GVHD among evaluable UCB recipients was lower than those of UBM and RPB recipients (32% vs. 54% vs. 59%, P < .01). Similarly, the incidences of chronic GVHD for evaluable UCB, UBM, and RPB recipients were 36%, 69%, and 66%, respectively (P < .01). The estimated overall survival (OS) and DFS rates at 5 years post-transplantation were 36% (95% confidence interval Åm95%CIÅn; 25 - 47%) and 35% (95%CI; 26 - 44%) for UCB, 55% (95%CI; 40 - 69%) and 51% (95%CI; 37 - 64%) for UBM, and 39% (95%CI; 22 - 55%) and 25% (95%CI; 8 - 41%) for RPB (OS, P < .01 and DFS, P < .01). In the standard group, OS and DFS rates were not significantly different in the three groups (OS, UCB 63% vs. UBM 70% vs. RPB 49%, P = .39 and DFS, UCB 63% vs. UBM 70% vs. RPB 39%, P = .10). Similarly, in the advanced group, there were not significantly difference in the three groups (OS, UCB 30% vs. UBM 41% vs. RPB 35%, P = .23 and DFS, UCB 29% vs. UBM 38% vs. RPB 24%, P = .27). Compared with UBM and RPB recipients, UCB recipients had delayed hematopoietic recovery at 60 day (UCB 85% vs. UBM 97% vs. RPB 100%, Hazard ratio ÅmHRÅn= 0.49; 95%CI: 0.40 0.59; P < .01). Five-year estimated TRM and relapse rate (RR) were not significantly different in the three groups (TRM, UCB 34% vs. UBM 29% vs. RPB 50%, P = .39 and RR, UCB 30% vs. UBM 20% vs. RPB 28%, P = .28). < Conclusion> In this analysis, there was no apparent difference in the risks of TRM and RR between the UCB and UBM/RPB recipient groups. OS and DFS in both groups were also comparable among standard and advanced groups. Finally, our clinical results suggest that UCBT could be as safe and effective a stem-cell source as UBMT or RPB transplant for adult AML/MDS patient. Disclosures: No relevant conflicts of interest to declare.

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.

Comparison of Outcomes of Bone Marrow and Umbilical Cord Blood Transplants from Unrelated Donors in Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2010-2010
Author(s):  
Kazuhiro Masuoka ◽  
Shigesaburo Miyakoshi ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract &lt;Objectives&gt; Promising results of cord blood transplants from unrelated donors have been reported in adults. To compare of outcomes of bone marrow transplants (BMT, n = 51), and umbilical cord blood transplants (UCBT, n = 110) from unrelated donors in adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS), we analyzed retrospectively the results of 161 adult patients with AML and MDS in our hospital. &lt;Patients and Methods&gt; We reviewed medical records of 161 patients with AML/MDS who had received a hematopoietic stem cell transplant from an unrelated donor between August 2000 and April 2007 at Toranomon Hospital, Tokyo, Japan. &lt;Results&gt; Patient’s median age was 55 years (17–71). Diagnoses include de novo AML (n =85), MDS overt AML (n=48), refractory anemia (RA) (n=13), and refractory anemia with excess of blasts (RAEB) (n=15). Disease status consisted of standard (CR1 of AML and RA, n=30) and advanced (other status, n=131). Recipients of UCBT had more advanced disease than recipients of BMT at the time of transplantation (89 percent vs. 65 percent, P&lt;0.001). The median number of nucleated cells that were infused was 0.26×108 per kilogram of the recipient’s body weight for cord blood and 2.5×108 per kilogram for bone marrow (P&lt;0.001). The major difference were higher number in the UCBT group of HLA mismatches (defined by serology for class 1 and molecular typing for DRB1).The donor was HLA mismatched in 96% of UCBT recipients, and in 41% of BMT recipients (P&lt;0.001). Other significant differences were observed in preparative regimens, and graft-versus-host disease (GVHD) prophylaxis. Nonadjusted estimates of 2-year OS and DFS rates were 53% and 48% in the BMT group, and 33% and 25% in the UCBT group (P&lt;0.001). However, 2-year OS and DFS rates in the standard group were not significantly different in the two groups (63% and 63% in the BMT group, and 75% and 58% in the UCBT group; p=0.98 and 0.32). Compared with BMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR]= 0.52; 95% confidence interval [95CI]: 0.36–0.75; p&lt;0.001), increased 100 day TRM (HR=3.07; 95CI 1.45–6.51; p&lt;0.01) and decreased grade II–IV acute graft-versus-host disease (aGVHD) (HR=0.58; 95CI 0.35–0.96; p=0.03). Two-year relapse rate was not significantly different in the two groups. &lt;Conclusion&gt; We conclude that UCBT from an unrelated donor is a therapeutic option for adult AML/MDS patients who lack an HLA-identical donors. Higher mortality, especially from non-relapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

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.

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.

scholarly journals Gene mutation spectrum of patients with myelodysplastic syndrome and progression to acute myeloid leukemia

2021 ◽  
pp. IJH34
Author(s):  
Ming Liu ◽  
Fang Wang ◽  
Yang Zhang ◽  
Xue Chen ◽  
Panxiang Cao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Sequencing Technology ◽  
Transcription Factor Genes ◽  
Spectrum Of Patients ◽  
Acute Myeloid

Aim: This study aimed to investigate the regularity of gene mutations in patients with myelodysplastic syndrome (MDS) and in those that progressed to acute myeloid leukemia (MDS/AML). Patients & methods: High-throughput sequencing technology was used to detect gene mutations in 99 newly diagnosed patients with MDS or MDS/AML. Results: Gene mutations were detected in 88 patients. The mutation incidence in the MDS/AML group was significantly higher than that in the MDS group. Statistically significant differences were observed between the MDS with refractory anemia (MDS-RA) and MDS-RA with excess blasts groups and between the MDS/AML and MDS-RA groups. Conclusion: Our data demonstrate that there is a cumulative accumulation of gene mutations, especially in transcription factor genes, during disease progression in MDS and MDS/AML.

scholarly journals Microvesicles microRNAs Reflect and Affect Progression of Acute Myeloid Leukemia and Could Serve As a Biomarker of Disease Dynamics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1664-1664
Author(s):  
Inna Tzoran ◽  
Annie Rebibo-Sabbah ◽  
Benjamin Brenner ◽  
Anat Aharon
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Healthy Controls ◽  
Disease Dynamics ◽  
Rt Pcr ◽  
Blast Cells ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is characterized by rapid growth of abnormal blast cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Microvesicles (MVs) are shedding from various cells and express antigens reflecting their cellular origin. Our previous study has demonstrated a correlation between the level of MVs originating from blast cells (CD117+ MVs) in the peripheral blood and the amount of CD117 positive blast cells in the bone marrow (BM) at diagnosis and in remission (r=0.49, p=0.0025; r=0.6, p=0.01; respectively). Additional assessment of CD117 expression on MVs obtained at diagnosis in patients who died despite achieving a remission revealed significantly higher values compared to those found in patients who were alive at 3 years of follow-up (1.9 vs. 0.6; p=0.01). A similar trend was found in CD34 positive MVs (1.2 vs. 0.13; p=0.01). It has, therefore, been concluded that circulating MVs of AML patients might serve as a biomarker of leukemia progression. MVs also contain cytokines and micro-RNA (miRNA) that are critical for cell development, proliferation and apoptosis. MVs are the major transport vehicle for miRNAs, and serve as a unique mode of genetic exchange between cells. To this end, several studies have shown that cancer stem cells regulate tumor environment through MVs. The current study aimed to explore the potential role of MV miRNAs as a biomarker of disease progression in AML and to study MV effects on the bone marrow leukemic niche. Methods: Blood and bone marrow samples were collected from healthy controls and patients with AML at diagnosis and upon achievement of first remission. MV effects on the BM mesenchymal stem cells (BM-MSC) and endothelial cells were studied using confocal microscopy, migration and proliferation assays and the RT-PCR method. miRNA expression was screened by NanoString technology and validated by RT-PCR. Results: The study was approved by the Institutional Review Board of the Rambam Health Care Campus (Approval #0351-10). Blood and bone marrow samples were collected from 43 AML patients and 4 random healthy volunteers after obtaining written informed consent. Sixty seven percent of patients remained alive and achieved remission following induction chemotherapy about one month after the diagnosis. Co-incubation of fluorescent-labeled BM-MVs (CD33+/CD117+) of AML patients with unlabeled BM-MSC resulted in incorporation of >80% of MVs to the cells. Patient BM-MVs of obtained at diagnosis induced a higher migration rate of BM-MSC compared to MVs obtained from healthy controls (p<0.01). Patient BM-MVs also induced a significantly higher proliferation rate of BM-MSC (p<0.05). Screening of patient BM-MVs demonstrated that the expression of some miRNAs was high at diagnosis but decreased in remission, while other miRNAs exhibited an opposite trend. Notably, these alterations were observed in miRNA-181a, that is known to play a role in normal and malignant hematopoiesis. Specifically, miRNA-181a levels in BM-MVs of AML patients were at least 10 times higher at diagnosis than in remission or in healthy controls (p<0.05). Similar results were found in miRNA-181a of circulating MVs of these patients, particularly in those who were alive at 1 year of follow-up. However, in patients that died within the first year, miRNA-181a expression at diagnosis was lower compared to healthy controls (2 times less, p=0.035) or to patients who were alive at the follow-up evaluation (7 times less, p= 0.0097). Co-incubation of BM-MSC with patient BM-MVs, obtained at diagnosis, resulted in a 4-time higher expression of miRNA-181a in these cells compared to untreated ones (p<0.05). Conclusion: MV-miRNAs of AML patients are involved in the regulation of tumor BM microenvironment, affecting BM-MSC migration, proliferation and gene expression. MV-miRNAs reflect and affect AML progression and may serve as a biomarker of disease dynamics. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document