Authors: OTSUKA, YUICHI; KONISHI, TOSHIRO¹; NARA, SATOSHI¹; FURUSHIMA, KAORU¹; NAKAJIMA, KENTARO¹; SHIMADA, HIROSHI²

Source: Journal of Gastroenterology and Hepatology, Volume 20, Number 9, September 2005 , pp. 1318-1321(4)

Publisher: Blackwell Publishing

A 50-year-old man was referred to our department with esophageal cancer. He had past history of small cell lung cancer treated with chemoradiation therapy 10 years prior. The disease was evaluated as complete remission after chemoradiation therapy and no recurrence had been observed. Esophagectomy accompanying postoperative chemotherapy was applied, but he died of secondary myelodysplastic syndrome with its acute myeloblastic transformation. Risk evaluation revealed a high incidence of esophageal cancer after radiation therapy and hematological malignancies after chemoradiation therapy in usual regimen with topoisomerase inhibitor or alkylating agents. Chemoradiation therapy is thought to be one of a few highly effective therapeutic alternatives and many complete remission cases have been reported in small cell lung cancer or esophageal cancer. In post-therapeutic follow up of patients with such past therapeutic histories, we should be cautious about secondary malignancies even if primary malignant disease was evaluated as complete remission in long past history.

Keywords: chemoradiation therapy; esophageal cancer; myelodysplastic syndrome; small cell lung cancer

Document Type: Research article

DOI: 10.1111/j.1440-1746.2005.03838.x

Affiliations: 1: Department of Surgery Kanto Medical Center NTT EC, Higashigotanda Shinagawa, Tokyo and 2: Gastroenterological Surgery (Second Department of Surgery), Yokohama City University, School of Medicine, Fukuura Kanazawa Yokohama, Kanagawa, Japan

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—      Istituto Nazionale Tumori, Milan (S. V., E. N., A. O., G. S., A. S.); Chair of Chemotherapy, University of Milan, (P. L., G. E., F. F.) Italy

Experimental studies have suggested that the pineal hormone melatonin, in addition to its documented antineoplastic action, plays a role in the physiological regulation of blood cell proliferation. Based on these data, we evaluated the clinical effects of melatonin therapy in patients with myelodysplastic syndrome (MDS) secondary to cancer chemotherapy for primary neoplasms. The study was carried out on six patients, and melatonin was given orally at a dose of 20 mg/daily, following a schedule prepared to reproduce the circadian rhythm of the pineal hormone. A transient improvement in platelet and neutrophil count was achieved in two of five patients with thrombocytopenia and in two of four patients with neutropenia before therapy, respectively, while no effect was seen on hemoglobin concentration. Mean survival time was 12.5 months, and a long survival, greater than 30 months, was achieved in two of six patients. These preliminary results seem to suggest that melatonin may have a role in the treatment of MDS induced by previous cancer chemotherapy.

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Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used.

Experimental Design: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing.

Results: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion.

Conclusions: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.

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Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31– clone in patients with this disorder.

Methods One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis.

Results Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide.

Conclusions Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov] .)

Source Information

From the University of South Florida College of Medicine and H. Lee Moffitt Cancer Center and Research Institute, Tampa (A.L.); Mayo Clinic, Rochester, MN (G.D.); University of Rochester, Rochester, NY (J.B.); St. Johannes Hospital, Duisberg, Germany (A.G.); University of Massachusetts, Worcester (A.R.); Cornell Medical Center, New York (E.F.); Wake Forest University, Winston-Salem, NC (B.P.); Stanford University, Stanford, CA (P.G.); M.D. Anderson Cancer Center, Houston (D.T.); Dana–Farber Cancer Institute, Boston (R.S.); Mayo Clinic, Scottsdale, AZ (C.R.); and Celgene Corporation, Warren, NJ (K.W., J.P., M.S., J.Z., R.K.).

Address reprint requests to Dr. List at the Malignant Hematology Division, SRB-4, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612-9497, or at heberten@moffitt.usf.edu

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Numerous studies have demonstrated a significant increase in apoptosis in patients having MDS using different methodologies.^7,8,9,10 The frequency and percentage of cells showing apoptosis in these patients vary depending on the methodology used and cell population analyzed. Apoptotic cell death can be measured by various methods including terminal dUTP nick-end labeling (TUNEL), caspase, annexin V and mitochondrial membrane potential. Each assay method measures a different component or event of apoptotic process. In this study, we used mitochondrial membrane potential measurement and annexin V assay as representative for early and advanced apoptosis.^11,12,13 Mitochondria has been shown to play a pivotal role in apoptosis in a number of ways, including the release of caspase activators, changes in electron transport and loss of mitochondrial transmembrane potential.^12,13 DePsipher is a dye that enters the mitochondria, polymerizes when the mitochondrial membrane potential is intact, and emits orange fluorescence; when the mitochondrial membrane potential is disturbed, the dye does not polymerize and emits green fluorescence.¹⁴ These two fluorescence colors can be analyzed by flow cytometry, and this assay can be used to detect early apoptosis. Annexin V allows identification of cell surface changes that occur during the apoptotic process. The binding of annexin V to phosphatidylserine on the damaged cell surface can be measured by flow cytometry. It is important to distinguish apoptotic cells from damaged cells as a result of non-apoptotic cell injury. In this study, we used PI in the four-color staining incubation mix to exclude cells that have lost membrane integrity, such as necrotic cells that may not reflect apoptotic process. Relatively lower estimates of apoptotic cells in this study compared to other studies that did not incorporated PI in the assay may be due to the exclusion of PI-positive cells in our annexin V assay. Furthermore, some studies⁷ used frozen samples and annexin V is significantly higher in frozen samples as compared with fresh samples.

Both mitochondrial potential and annexin V assays showed higher degree of apoptosis in RAEB-T as compared to AML. The possibility that the increase in apoptosis in MDS and RAEB-T cases could be due to increased percentage of mature and maturing cells should be considered and for this reason, we analyzed apoptosis in CD34⁺ cells separately from mature neutrophils. Higher apoptosis was observed in both CD34⁺ cells, as well as in CD34^- cells by annexin V assay. Similarly, higher apoptosis was present in both polymorphonuclear cells and mononuclear cells assessed by mitochondrial potential assay. Thus, apoptosis is not merely a function of the percentage of blasts in the bone marrow. Our findings are consistent with those of Raza et al^4,5 who demonstrated a high degree of apoptosis in bone marrow biopsies from patients with MDS.

We observed particularly increased apoptosis in CMML using mitochondrial potential. Overall, there was significant correlation between mitochondrial potential and annexin V in detecting apoptosis in CMML, as well as in all other subgroups. The disturbance in the mitochondrial potential is the earliest change in the apoptotic pathway. In contrast, annexin V positivity is a late phenomenon. The relatively higher apoptosis in CMML, which is detected by mitochondrial potential may reflect difference in the stage of apoptosis and how apoptotic cells are cleared.

Measurement of apoptosis is particularly influenced by the method of processing, time to processing, and other physiologic factors. Although we have made every effort to process samples in a similar fashion as soon as possible and many samples were analyzed in duplicate, we cannot rule out the possibility of variation due to the methodology of the assays. The high number of cases analyzed and the consistent results obtained using two different methodologies, support our conclusions.

Most published studies did not separate RAEB-T from other subgroups of MDS in their analysis. Specifically, one study that grouped RAEB-T with secondary AML (MDS-AML) showed a significantly lesser degree of apoptosis in patients having RAEB-T/MDS-AML compared with those having RA/RARS and RAEB.⁹ Our group recently reported a significantly higher degree of apoptosis in patients having RAEB-T compared with those having AML as assessed according to their caspase 3 activity (P = 0.0001).¹⁰ In that study, the caspase 3 activity in RAEB-T patients did not differ significantly from that in patients having other MDS. In addition, RAEB-T was distinguished from AML with respect to several laboratory and clinical parameters. In particular, RAEB-T patients had a higher proliferating rate and tend to have a lower platelet count and bone marrow cellularity as compared with AML patients.¹⁰

The data presented here support the concept that MDS disease is a disease of ineffective hematopoiesis and the reason for the ineffective hematopoiesis is increased cell death in bone marrow. In contrast, AML is a disease of proliferation of immature cells (blasts). Both diseases are clonal. In MDS, leukemic cells are capable of differentiating while in AML, usually leukemic cells do not differentiate. There is certainly some overlap between MDS and AML in the level of apoptosis. Patients classified as RAEB-T may include those having AML who were detected at an early stage, and similarly some AML patients with a blast count higher than 30% may have higher degree of apoptosis, therefore biologically closer to MDS. Our data suggest that perhaps neither 20% nor 30% blasts is a magic cut-off point to distinguish AML from MDS, but overall RAEB-T is biologically closer to MDS than AML. Irrespective of the cut-off point, therapy should take into consideration the biological and cellular abnormalities in AML and MDS and exploit these abnormalities either to kill the leukemic cells or correct the environment that allow these cells to dominate. Currently, outcome of RAEB-T patients may not be significantly different from that of AML, however, as we develop new therapies that specifically target the biological and molecular abnormalities in leukemic cells, we may start seeing differences between AML and MDS. Elimination of the RAEB-T category by lumping it in with AML does not achieve any goal and does not advance our understanding or management of AML nor MDS.

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JENKINTOWN, Pa., February 26, 2007 — The National Comprehensive Cancer Network (NCCN) announces important updates to the NCCN Myelodysplastic Syndromes (MDS) Guidelines. The NCCN Clinical Practice Guidelines in Oncology™ are widely recognized and applied as the standard of care in oncology in the United States in both the community and the academic practice settings. These guidelines are updated continually and are based upon evaluation of scientific data integrated with expert judgment.

One of the major changes to the 2007 version of the guidelines was the addition of darbepoetin alfa (Aranesp®, Amgen) as a recommendation for anemic patients with low-intermediate risk MDS. Studies indicate that darbepoetin is an active, safe and well-tolerated treatment for anemia offering patients an overall improvement in quality of life.

The panel also added single agents azacytidine (Vidaza®, Pharmion) and decitabine (Dacogen™, MGI Pharma) to the guidelines as primary treatment for patients with INT-2 and high-risk MDS who are intensive therapy candidates but have no available donor for hemopoietic stem cell transplant.

NCCN Clinical Practice Guidelines in Oncology™ are developed and updated through an evidence-based process with explicit review of the scientific evidence by multidisciplinary panels of expert physicians from NCCN Member Institutions. The most recent version of this and all the guidelines are available free of charge at www.nccn.org.

For questions about NCCN or for interview information, please contact Thomas Mitchell at 215.690.0245.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.nccn.org.

The NCCN Member Institutions are:

—      City of Hope

—      Dana-Farber/Brigham and Women’s Cancer Center

—      Massachusetts General Hospital Cancer Center

—      Duke Comprehensive Cancer Center

—      Fox Chase Cancer Center

—      Huntsman Cancer Institute at the University of Utah

—      Fred Hutchinson Cancer Research Center / Seattle Cancer Care Alliance

—      Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University

—      The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

—      Robert H. Lurie Comprehensive Cancer Center of Northwestern University

—      Memorial Sloan-Kettering Cancer Center

—      H. Lee Moffitt Cancer Center & Research Institute

—      Roswell Park Cancer Institute

—      Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

—      St. Jude Children’s Research Hospital / University of Tennessee Cancer Institute

—      Stanford Comprehensive Cancer Center

—      University of Alabama at Birmingham Comprehensive Cancer Center

—      UCSF Helen Diller Family Comprehensive Cancer Center

—      University of Michigan Comprehensive Cancer Center

—      UNMC Eppley Cancer Center at The Nebraska Medical Center

—      The University of Texas M. D. Anderson Cancer Center

—      Vanderbilt-Ingram Cancer Center

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Treatment of de novo myelodysplastic syndromes may include the following:

—      Supportive care with transfusion therapy.

—      High-dose chemotherapy with stem cell transplant using stem cells from a donor.

—      Supportive care with growth factor therapy.

—      Chemotherapy with azacitidine, decitabine, or other anticancer drugs.

—      Supportive care with drug therapy.

—      A clinical trial of a new anticancer drug.

—      A clinical trial of low- dose chemotherapy with stem cell transplant using stem cells from a donor.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site ¹.

Check for clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with de novo myelodysplastic syndromes ².

Secondary Myelodysplastic Syndromes

Treatment of secondary myelodysplastic syndromes may include the following:

—      Supportive care with transfusion therapy.

—      Supportive care with growth factor therapy.

—      Chemotherapy with azacitidine or other anticancer drugs.

—      Chemotherapy with stem cell transplant using stem cells from a donor.

—      A clinical trial of chemotherapy.

—      A clinical trial of low- dose chemotherapy with stem cell transplant using stem cells from a donor.

—      A clinical trial of supportive care with drug therapy.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site ¹.

Check for clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with secondary myelodysplastic syndromes ³.

Previously Treated Myelodysplastic Syndromes

Treatment of previously treated myelodysplastic syndromes may include the following:

—      High-dose chemotherapy with stem cell transplant using stem cells from a donor.

—      Chemotherapy with azacitidine or decitabine.

—      Supportive care with transfusion therapy, growth factor therapy, and/or drug therapy.

—      A clinical trial of low- dose chemotherapy with stem cell transplant using stem cells from a donor.

—      A clinical trial of new drug therapy.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site ¹.

Check for clinical trials from NCI’s PDQ Cancer Clinical Trials Registry that are now accepting patients with previously treated myelodysplastic syndromes ⁴.

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Takahiro Nagashima^1,2, Kazuo Muroi^1,2, Masae Kunitama¹, Tohru Izumi¹, Tetsuya Ohtsuki¹, Norio Komatsu¹, Masashi Fukayama³ and Keiya Ozawa

¹Division of Hematology, Department of Medicine, ²Division of Cell Transplantation and Transfusion and ³Department of Pathology, Jichi Medical School, Tochigi, Japan

A 59-year-old man was admitted to our hospital because of disturbance of consciousness and hyponatremia. The patient had suffered from acute myelogenous leukemia (AML) with 46,XY and received chemotherapy for 5 years. Meningeal carcinomatosis was diagnosed due to the detection of carcinoma cells in the cerebrospinal fluid (CSF). Hyponatremia was caused by syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Bone marrow examination revealed myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 7. Emergence of a new abnormal clone was suggested. The patient died from brain herniation. Post mortem examination showed adenocarcinoma in the colon. An association between chemotherapy and both colon cancer and MDS was suggested.

Introduction
Second neoplasms are known to be early and late complications in patients with leukemias and lymphomas following chemotherapy and irradiation. The use of alkylating agents and topoisomerase 2 inhibitors is associated with the development of therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (1–4). In contrast, the risk of developing therapy-related solid tumors is associated mainly with the use of radiation therapy in patients with Hodgkin’s disease (5). We present here a unique case of second neoplasms in which the patient had received chemotherapy to treat AML for 5 years and subsequently developed colon cancer with meningeal carcinomatosis and MDS simultaneously.

Case Report

A 55-year-old man was admitted to the Jichi Medical School Hospital because of fatigue and bleeding tendency in January 1993. He was diagnosed as having AML (FAB classification, AML-M4). Chromosome analysis of bone marrow cells showed 46,XY (30/30 cells). After induction chemotherapy by the JALSG–AML92 protocol (enocitabine, etoposide, daunorubicin and 6-mercaptopurine) (6), he achieved complete remission. He was then treated with three courses of consolidation chemotherapy (first course, mitoxantrone and cytarabine; second, enocitabine, etoposide, daunorubicin and 6-mercaptopurine; third, enocitabine and aclarubicin), until November 1993, but the treatment was complicated by severe bacterial sepsis and cellulitis. To prevent severe infection due to intensive chemotherapy-induced neutropenia, his treatment was continued with low-dose chemotherapy including cytarabine, 6-mercaptopurine, cytarabine ocfosfate and etoposide monthly until April 1998. The cumulative dose of etoposide was 4870 mg. In September 1996, bone marrow aspiration had revealed complete remission with normal karyotype (9/9 cells).

In May 1998, he experienced nausea, general fatigue and tarry stool. Therefore, he visited his local physician. Peripheral blood analysis showed a normal blood cell count. The serum sodium concentration was 127 mmol/l and the levels of thyroid hormones, aldosterone and cortisol were normal. The results of fiberscopic examination of the upper gastrointestinal tract were normal. His consciousness gradually deteriorated. Computed tomography (CT) of the patient’s head showed no bleeding, infarction or tumors. He was transferred to our hospital on June 3, 1998.

Physical examination showed no lymphadenopathy or hepatosplenomegaly. Neurological examination revealed stiff neck. Peripheral blood showed a white blood cell count of 6800/µl with 8% stab, 76% segment, 3% monocytes and 13% lymphocytes, a hemoglobin concentration of 12.1 g/dl and a platelet count of 13.0 x 10⁴/µl. Serum lactate dehydrogenase (LDH) level was normal but carcinoembryonic antigen (CEA) and CA19-9 levels were markedly elevated (1613 ng/ml and 43 820 U/ml, respectively). Serum sodium concentration was low (121 mmol/l) and both serum and plasma osmolarity were low (240 and 243 mOsm, respectively). Serum creatinine level was normal. Urinalysis showed a high specific gravity (1.042) and hyperosmolarity (779 mOsm). Taken together with serum and urine data, diagnosis of syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) was made.

On June 4, he received lumbar puncture to rule out meningeal infiltration of leukemic cells. The cerebrospinal fluid (CSF) revealed monocytic pleocytosis, high protein and low sugar concentrations and increased levels of LDH (967 IU/l) and CEA (4820 ng/ml). Cytospin preparations showed large atypical mononuclear cells, which had abundant and basophilic cytoplasm without granules. Nuclei were round and eccentrically placed with nucleoli (Fig. 1A). The periodic acid–Schiff (PAS) reaction was strongly positive (Fig. 1B). Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed linear enhancement of the leptomeninges and enlargement of the cerebral ventricles. The patient was diagnosed as having meningeal carcinomatosis. Results of CT of the chest and ultrasonography of the abdomen were normal. Bone marrow aspiration revealed no proliferation of blasts and mild cellular atypism in neutrophils, erythroblasts and megakaryocytes (Fig. 2). Chromosomal analysis of bone marrow cells revealed deletion of the long arm of chromosome 7 (9/30 cells). He was diagnosed as having MDS.

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The prevalence of patients with myelodysplastic syndromes (MDS) is increasing owing to an ageing population and increased awareness of these diseases. MDS represent many different conditions, not just a single disease, that are grouped together by several clinical characteristics. A striking feature of MDS is genetic instability, and a large proportion of cases result in acute myeloid leukaemia (AML). We Review three emerging principles of MDS biology: stem-cell dysfunction and the overlap with AML, genetic instability and the deregulation of apoptosis, in the context of inherited bone marrow-failure syndromes, and treatment-related MDS and AML

Author affiliations

1.        Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

2.        Division of Pediatrics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

3.        Division of Hematology and Oncology, Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, Ontario, Canada.

4.        Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto, Ontario, Canada.

5.        Division of Cell and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada.

6.        Division of Genomics and Proteomics, Ontario Cancer Institute, Toronto, Ontario, Canada.

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(MDS, formerly known as “preleukemia”) are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelog