DOCSLIB.ORG

Acute Promyelocytic Leukemia Facts

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Acute Promyelocytic Leukemia Facts Acute Promyelocytic Leukemia Facts No. 26 in a series providing the latest information for patients, caregivers and healthcare professionals Highlights About AML y Acute promyelocytic leukemia (APL) is a unique Leukemia is a cancer of the marrow and blood. subtype of acute myeloid leukemia (AML). The four major types of leukemia are acute myeloid APL cells have a very specific abnormality that leukemia (AML), chronic myeloid leukemia (CML), involves chromosomes 15 and 17, leading to the acute lymphoblastic leukemia (ALL) and chronic formation of an abnormal fusion gene called lymphocytic leukemia (CLL). Each of the main types PML/RARα. This mutated gene causes many of of leukemia is further classified into subtypes. Acute the features of the disease. promyelocytic leukemia (APL) is a unique subtype of AML (approximately 600-800 new cases each year y Promyelocytes are immature white blood in the US). cells. In APL, these cells are overproduced and accumulate in the bone marrow. Signs, In myeloid leukemia, a cancerous change begins in symptoms and complications of APL result from the bone marrow, in a stem cell that normally would the overproduction of promyelocytes and the develop into a blood cell—a red blood cell, some type underproduction of healthy blood cells. of white blood cell or a platelet. y Treatment with a drug called all-trans retinoic Acute promyelocytic leukemia (APL) gets its name acid (ATRA) targets chromosomal abnormality. from immature white blood cells called promyelocytes Arsenic trioxide (ATO) as a single agent has that accumulate in the marrow and crowd out other also proven successful in APL treatment. healthy cells. These cells are myeloblasts that have The combination of ATRA and ATO has been stopped maturing. (Healthy myeloblasts turn into FDA-approved for the treatment of adults with myelocytes and eventually become mature white newly diagnosed low-risk disease characterized blood cells called granulocytes: neutrophils, basophils, by the presence of the t(15;17) translocation and eosinophils). or PML/RARα gene expression. Other drug therapies that have increased remission APL cells have a specific chromosome abnormality and cure rates include anthracyclines and that involves a translocation of chromosome 15 and gemtuzumab ozogamicin (GO). chromosome 17, abbreviated as t(15;17), which creates an abnormal fusion gene called PML/RARα. This y Because of advances in diagnosis and treatment abnormality is present in about 95 percent of patients of this disease, APL is now considered the most diagnosed with APL. curable form of adult leukemia. Cure rates of 90 percent have been reported from centers The World Health Organization (WHO) classification specializing in APL treatment. is the main system used to classify AML into subtypes. The WHO developed this system to include chromosomal abnormalities and genetic mutations, which are known to affect prognosis (the likely outcome of the disease). These genetic factors help provide both doctor and patient with more reliable information about the patient’s prognosis and also help predict the patient’s response to treatment. Information about a person’s AML subtype helps the doctor recommend a specific treatment plan. The WHO classification is usually revised every eight years. The revised 2016 classification incorporates FACT SHEET Acute Promyelocytic Leukemia Facts new scientific and clinical information (see Table 1, Cancer Institute (NCI) SEER (Surveillance, Epidemiology, below). For the full WHO AML classification, and End Results Program) registry, for the period from please visit www.LLS.org/booklets to see the free 2013 to 2017, the age-adjusted annual incidence of booklet Acute Myeloid Leukemia. newly diagnosed cases was 0.34 per 100,000 persons— about 1 case per 294,000 persons. During that period, Table 1. World Health Organization AML Classification the median age of APL diagnosis was 51 years. The medial age of AML diagnosis is 68 years. Hispanics Acute Myeloid Leukemia (AML) and Related Neoplasms have the highest incidence rate of APL, while Asian and AML with Recurrent Genetic Inversion and/or Pacific Islanders have the lowest rate. Gene Abnormalities Translocation With current treatment, APL has become one of the most AML with t(8;21)(q22;q22.1)1 RUNX1-RUNX1T1 curable types of acute leukemia. People with APL who inv(16)(p13.1q22) or AML with CBFB-MYH11 receive treatment often have a normal or near-normal t(16;16)(p13.1;q22) quality of life. Acute promyelocytic t(15:17) PML-RAR leukemia (APL) α Please visit www.LLS.org/booklets to see the free LLS AML with t(9;11)(p21.3;q23.3) MLLT3-KMT2A booklet Understanding Genetics. AML with t(6;9)(p23;q34.1) DEK-NUP214 inv(3)(q21.3q26.2) or GATA2, AML with Signs and Symptoms t(3;3)(q21.3;q26.2) MECOM(EV11) It is common for people with APL to feel a loss of well- AML (megakaryoblastic) with t(1;22)(p13.3;q13.3) RBM15-MKL1 being because of the underproduction of normal blood AML with N/A mutated NPM1 cells as well as with the accumulation of leukemic cells Biallelic mutations AML with N/A in the bone marrow. of CEBPA Source: World Health Organization (WHO) classification. WHO categorizes AML Common signs and symptoms of APL include into groups based on recent discoveries in cytogenetic and clinical features of AML. Abbreviations: t, a translocation between chromosomes; inv, an inversion in a chromosome; q, the long arm of a chromosome (the lower half); p, the short arm y Pale complexion, caused by anemia of a chromosome (the upper half). y Signs of bleeding caused by a very low platelet count, including Treatment for APL differs from all other AML treatments. Because of advances in diagnosis and treatment, {{Black-and-blue marks or bruises occurring for no APL has been transformed from the most fatal to the reason or because of a minor injury most curable form of acute leukemia in adults. {{The appearance of pinhead-sized red spots This Fact Sheet provides current information about on the skin, called “petechiae” diagnosis, treatment, and new treatments being {{Prolonged bleeding from minor cuts investigated in clinical trials, along with support resources. y Fatigue Causes and Incidence y Mild fever Most APL cells have a specific chromosome abnormality y Swollen gums involving a balanced translocation (swapping) between y Frequent minor infections chromosomes 15 and 17 t(15;17), resulting in the y Loss of appetite abnormal fusion gene PML/RARα. This abnormality is a distinguishing feature of APL that causes the symptoms y Weight loss of the disease; it is also a key target of treatment. y Discomfort in bones or joints Among adults over age 20, APL represents y Enlarged spleen and liver approximately 7 percent of AML cases. There are approximately 1,100 new cases of APL each year in y Neurologic symptoms such as headache, confusion the United States. According to data from the National and visual changes (associated with APL that involves the central nervous system [CNS]) 2 Acute Promyelocytic Leukemia Facts Bleeding. A low platelet count and low amounts of clotting from the overproduction of promyelocytes and the factors predispose patients to bleeding. In addition, underproduction of healthy blood cells. patients with high white blood cell (WBC) counts at Doctors use the results of blood and bone marrow tests diagnosis are at increased risk for bleeding. Bleeding in to identify abnormal APL cells. A prompt diagnosis of APL the brain or lungs is serious and can be fatal. This kind of is vital because appropriate treatment must be started serious bleeding is usually preceded by minor bleeding, immediately in order to avoid the serious and potentially such as nosebleeds, blood in the urine, or bruises. life-threatening complications (especially bleeding in the Infection. Severe infection may be present at the time brain or lungs) associated with the disease. of diagnosis for some patients, due to low white blood Coagulation Tests. When APL is suspected, doctors cell counts. Infection may become more common may order “coagulation status” tests along with other and often more serious during treatment, when the laboratory tests and imaging scans, to help assess the bone marrow is completely suppressed. clotting status of the patient’s blood. Coagulation refers to the blood’s ability to form clots when necessary. This Diagnosis process is impaired in APL patients because patients When a patient is suspected of having leukemia, have fewer platelets and clotting factors in the blood. obtaining an accurate diagnosis of the type of leukemia Coagulation disorders can lead to heavy and prolonged is important. The exact diagnosis helps the doctor bleeding after an injury. Coagulation tests help prevent estimate how the disease will progress and determine or diagnose serious conditions such as deep-vein the appropriate course of treatment. Some of the tests thrombosis, pulmonary embolism and strokes. See the used for making a diagnosis may also be repeated Glossary on page 9 for more information on these terms. during and after therapy to measure the effects of Please visit www.LLS.org/booklets to see the free LLS treatment. booklet Understanding Lab and Imaging Tests. Blood and Bone Marrow Tests. A change in the number and appearance of blood cells helps the doctor make an Treatment Planning accurate diagnosis. APL cells may look similar to normal Treatment decisions are based on the patient’s age, immature white cells. However, their development is general health and APL risk classification. incomplete. APL is classified into the two following categories Blood samples are generally taken from a vein in the of risk, based on the patient’s white blood cell count patient’s arm. Samples of marrow cells are obtained at diagnosis: by bone marrow aspiration and biopsy.
Load more

Recommended publications
  • Updates in Mastocytosis
    Updates in Mastocytosis Tryptase PD-L1 Tracy I. George, M.D. Professor of Pathology 1 Disclosure: Tracy George, M.D. Research Support / Grants None Stock/Equity (any amount) None Consulting Blueprint Medicines Novartis Employment ARUP Laboratories Speakers Bureau / Honoraria None Other None Outline • Classification • Advanced mastocytosis • A case report • Clinical trials • Other potential therapies Outline • Classification • Advanced mastocytosis • A case report • Clinical trials • Other potential therapies Mastocytosis symposium and consensus meeting on classification and diagnostic criteria for mastocytosis Boston, October 25-28, 2012 2008 WHO Classification Scheme for Myeloid Neoplasms Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic Leukemia Myelodysplastic Syndromes MDS/MPN, unclassifiable Chronic Myelogenous Leukemia MDS/MPN Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis Myeloproliferative Neoplasms Chronic Neutrophilic Leukemia Chronic Eosinophilic Leukemia, NOS Hypereosinophilic Syndrome Mast Cell Disease MPNs, unclassifiable Myeloid or lymphoid neoplasms Myeloid neoplasms associated with PDGFRA rearrangement associated with eosinophilia and Myeloid neoplasms associated with PDGFRB abnormalities of PDGFRA, rearrangement PDGFRB, or FGFR1 Myeloid neoplasms associated with FGFR1 rearrangement (EMS) 2017 WHO Classification Scheme for Myeloid Neoplasms Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic
    [Show full text]
  • WO 2017/177167 Al 12 October 2017 (12.10.2017) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/177167 Al 12 October 2017 (12.10.2017) P O P C T (51) International Patent Classification: (26) Publication Language: English Λ 61Κ 31/192 (2006.01) A61K 31/551 (2006.01) (30) Priority Data: A61K 31/167 (2006.01) A61K 31/553 (2006.01) 62/320,352 8 April 2016 (08.04.2016) US A61K 31/232 (2006.01) A61K 31/573 (2006.01) A61K 31/235 (2006.01) A61K 31/69 (2006.01) (71) Applicant: SYROS PHARMACEUTICALS, INC. A61K 31/25 (2006.01) A61K 31/695 (2006.01) [US/US]; 620 Memorial Drive, Suite 300, Cambridge, A61K 31/353 (2006.01) A61K 31/704 (2006.01) Massachusetts 02139 (US). A61K 31/40 (2006.01) A61K 31/706 (2006.01) A61K 31/4025 (2006.01) A61K 31/7068 (2006.01) (72) Inventors: MCKEOWN, Michael Robert; 74 Fenway, A61K 31/4155 (2006.01) A61K 33/24 (2006.01) #54, Boston, Massachusetts 021 15 (US). FIORE, Chris¬ A61K 31/426 (2006.01) A61K 33/36 (2006.01) topher; 620 Memorial Drive, Suite 300, Cambridge, Mas A61K 31/44 (2006.01) A61K 45/06 (2006.01) sachusetts 02 139 (US). EATON, Matthew Lucas; 90 Put A61K 31/4436 (2006.01) A61P 35/00 (2006.01) nam Avenue, #4, Cambridge, Massachusetts 02139 (US). A61K 31/498 (2006.01) A61P 35/02 (2006.01) LEE, Emily Payton; 1 Craigie Street, Apt. 35, Cambridge, A61K 31/519 (2006.01) A61P 35/04 (2006.01) Massachusetts 02138 (US).
    [Show full text]
  • The Clinical Management of Chronic Myelomonocytic Leukemia Eric Padron, MD, Rami Komrokji, and Alan F
    The Clinical Management of Chronic Myelomonocytic Leukemia Eric Padron, MD, Rami Komrokji, and Alan F. List, MD Dr Padron is an assistant member, Dr Abstract: Chronic myelomonocytic leukemia (CMML) is an Komrokji is an associate member, and Dr aggressive malignancy characterized by peripheral monocytosis List is a senior member in the Department and ineffective hematopoiesis. It has been historically classified of Malignant Hematology at the H. Lee as a subtype of the myelodysplastic syndromes (MDSs) but was Moffitt Cancer Center & Research Institute in Tampa, Florida. recently demonstrated to be a distinct entity with a distinct natu- ral history. Nonetheless, clinical practice guidelines for CMML Address correspondence to: have been inferred from studies designed for MDSs. It is impera- Eric Padron, MD tive that clinicians understand which elements of MDS clinical Assistant Member practice are translatable to CMML, including which evidence has Malignant Hematology been generated from CMML-specific studies and which has not. H. Lee Moffitt Cancer Center & Research Institute This allows for an evidence-based approach to the treatment of 12902 Magnolia Drive CMML and identifies knowledge gaps in need of further study in Tampa, Florida 33612 a disease-specific manner. This review discusses the diagnosis, E-mail: [email protected] prognosis, and treatment of CMML, with the task of divorcing aspects of MDS practice that have not been demonstrated to be applicable to CMML and merging those that have been shown to be clinically similar. Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hemato- logic malignancy characterized by absolute peripheral monocytosis, ineffective hematopoiesis, and an increased risk of transformation to acute myeloid leukemia.
    [Show full text]
  • Preparation and Antitumor Activity of a Tamibarotene-Furoxan Derivative
    DOI:http://dx.doi.org/10.7314/APJCP.2014.15.15.6343 Preparation and Anti-tumor Activity of a Tamibarotene-Furoxan Derivative RESEARCH ARTICLE Preparation and Antitumor Activity of a Tamibarotene- Furoxan Derivative Xue-Jian Wang1&*, Yu Duan1&, Zong-Tao Li2, Jin-Hong Feng3, Xiang-Po Pan4, Xiu-Rong Zhang1, Li-Hong Shi1, Tao Zhang2* Abstract Multi-target drug design, in which drugs are designed as single molecules to simultaneously modulate multiple physiological targets, is an important strategy in the field of drug discovery. QT-011, a tamibarotene-furoxan derivative, was here prepared and proposed to exert synergistic effects on antileukemia by releasing nitric oxide and tamibarotene. Compared with tamibarotene itself, QT-011 displayed stronger antiproliferative effects on U937 and HL-60 cells and was more effective evaluated in a nude mice U937 xenograft model in vivo. In addition, QT-011 could release nitric oxide which might contribute to the antiproliferative activity. Autodocking assays showed that QT-011 fits well with the hydrophobic pocket of retinoic acid receptors. Taken together, these results suggest that QT-011 might be a highly effective derivative of tamibarotene and a potential candidate compound as antileukemia agent. Keywords: Tamibarotene - NO donor - anti-tumor compound - retinoic acid receptors Asian Pac J Cancer Prev, 15 (15), 6343-6347 Introduction the combined treatment with RAR agonists (e.g., ATRA) and histone deacetylase inhibitors (e.g., butyrate, valproic Retinoids, which have been successfully used in the acid, SAHA, FK228, MS-275, and TSA) can remarkably control and treatment of cancer, can serve as in vivo ligands improve efficacy, reduce side effects, and decrease retinoid of retinoic acid receptors (RARs) or retinoid X receptors resistance against acute leukemia (e.g., APL) (Warrell, Jr.
    [Show full text]
  • Philadelphia Chromosome Unmasked As a Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment
    Letters to the Editor 2050 The ELL/MLLT1 dual-color assay described herein entails 3Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA, USA and co-hybridization of probes for the ELL and MLLT1 gene regions, 4 each labeled in a different fluorochrome to allow differentiation Cytogenetics Laboratory, Seattle Cancer Care Alliance, between genes involved in 11q;19p chromosome translocations Seattle, WA, USA E-mail: [email protected] in interphase or metaphase cells. In t(11;19) acute leukemia cases, gain of a signal easily pinpoints the specific translocation breakpoint to either 19p13.1 or 19p13.3 and 11q23. In the References re-evaluation of our own cases in light of the FISH data, the 19p breakpoints were re-assigned in two patients, underscoring a 1 Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A certain degree of difficulty in determining the precise 19p et al. Cytogenetic of multiple myeloma: interpretation of fluorescence in situ hybridization results. Br J Haematol 2003; 120: 944–952. breakpoint in acute leukemia specimens in the context of a 2 Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD. clinical cytogenetics laboratory. Furthermore, we speculate that Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) the ELL/MLLT1 probe set should detect other 19p translocations in acute myeloid leukemia. Proc Natl Acad Sci 1994; 91: 12110– that involve these genes with partners other than MLL. Accurate 12114. molecular classification of leukemia is becoming more im- 3 Tkachuk DC, Kohler S, Cleary ML.
    [Show full text]
  • August 2019: Additions and Deletions to the Drug Product List
    Prescription and Over-the-Counter Drug Product List 39TH EDITION Cumulative Supplement Number 08 : August 2019 ADDITIONS/DELETIONS FOR PRESCRIPTION DRUG PRODUCT LIST ACETAMINOPHEN; BENZHYDROCODONE HYDROCHLORIDE TABLET;ORAL APADAZ >D> + KVK TECH INC 325MG;EQ 8.16MG BASE N 208653 003 Jan 04, 2019 Aug CHRS >A> +! 325MG;EQ 8.16MG BASE N 208653 003 Jan 04, 2019 Aug CHRS ACETAMINOPHEN; CODEINE PHOSPHATE TABLET;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >A> AA ELITE LABS INC 300MG;15MG A 212418 001 Sep 10, 2019 Aug NEWA >A> AA 300MG;30MG A 212418 002 Sep 10, 2019 Aug NEWA >A> AA 300MG;60MG A 212418 003 Sep 10, 2019 Aug NEWA ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE TABLET;ORAL OXYCODONE AND ACETAMINOPHEN >D> AA CHEMO RESEARCH SL 325MG;5MG A 207574 001 Dec 13, 2016 Aug CAHN >A> AA HALO PHARM CANADA 325MG;5MG A 207834 001 Aug 15, 2019 Aug NEWA >A> AA 325MG;7.5MG A 207834 002 Aug 15, 2019 Aug NEWA >A> AA 325MG;10MG A 207834 003 Aug 15, 2019 Aug NEWA >A> AA XIROMED 325MG;5MG A 207574 001 Dec 13, 2016 Aug CAHN ACYCLOVIR CAPSULE;ORAL ACYCLOVIR >A> AB CADILA 200MG A 204313 001 Mar 25, 2016 Aug CAHN >D> AB ZYDUS PHARMS 200MG A 204313 001 Mar 25, 2016 Aug CAHN >D> OINTMENT;OPHTHALMIC >D> AVACLYR >D> +! FERA PHARMS LLC 3% N 202408 001 Mar 29, 2019 Aug DISC >A> + @ 3% N 202408 001 Mar 29, 2019 Aug DISC OINTMENT;TOPICAL ACYCLOVIR >A> AB APOTEX INC 5% A 210774 001 Sep 06, 2019 Aug NEWA >D> AB PERRIGO UK FINCO 5% A 205659 001 Feb 20, 2019 Aug DISC >A> @ 5% A 205659 001 Feb 20, 2019 Aug DISC ALBENDAZOLE TABLET;ORAL ALBENDAZOLE >A> AB STRIDES PHARMA 200MG A 210011
    [Show full text]
  • Research in Your Backyard Developing Cures, Creating Jobs
    Research in Your Backyard Developing Cures, Creating Jobs PHARMACEUTICAL CLINICAL TRIALS IN ILLINOIS Dots show locations of clinical trials in the state. Executive Summary This report shows that biopharmaceutical research com- Quite often, biopharmaceutical companies hire local panies continue to be vitally important to the economy research institutions to conduct the tests and in Illinois, and patient health in Illinois, despite the recession. they help to bolster local economies in communities all over the state, including Chicago, Decatur, Joliet, Peoria, At a time when the state still faces significant economic Quincy, Rock Island, Rockford and Springfield. challenges, biopharmaceutical research companies are conducting or have conducted more than 4,300 clinical For patients, the trials offer another potential therapeutic trials of new medicines in collaboration with the state’s option. Clinical tests may provide a new avenue of care for clinical research centers, university medical schools and some chronic disease sufferers who are still searching for hospitals. Of the more than 4,300 clinical trials, 2,334 the medicines that are best for them. More than 470 of the target or have targeted the nation’s six most debilitating trials underway in Illinois are still recruiting patients. chronic diseases—asthma, cancer, diabetes, heart dis- ease, mental illnesses and stroke. Participants in clinical trials can: What are Clinical Trials? • Play an active role in their health care. • Gain access to new research treatments before they In the development of new medicines, clinical trials are are widely available. conducted to prove therapeutic safety and effectiveness and compile the evidence needed for the Food and Drug • Obtain expert medical care at leading health care Administration to approve treatments.
    [Show full text]
  • Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell
    Hindawi Publishing Corporation Case Reports in Hematology Volume 2012, Article ID 875039, 6 pages doi:10.1155/2012/875039 Case Report Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature Diana O. Treaba,1 Salwa Khedr,1 Shamlal Mangray,1 Cynthia Jackson,1 Jorge J. Castillo,2 and Eric S. Winer2 1 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA 2 Division of Hematology/Oncology, The Miriam Hospital, The Warren Alpert Medical School, Brown University, Providence, RI 02904, USA Correspondence should be addressed to Diana O. Treaba, [email protected] Received 2 April 2012; Accepted 21 June 2012 Academic Editors: E. Arellano-Rodrigo, G. Damaj, and M. Gentile Copyright © 2012 Diana O. Treaba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML.
    [Show full text]
  • Mirna182 Regulates Percentage of Myeloid and Erythroid Cells in Chronic Myeloid Leukemia
    Citation: Cell Death and Disease (2017) 8, e2547; doi:10.1038/cddis.2016.471 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cddis MiRNA182 regulates percentage of myeloid and erythroid cells in chronic myeloid leukemia Deepak Arya1,2, Sasikala P Sachithanandan1, Cecil Ross3, Dasaradhi Palakodeti4, Shang Li5 and Sudhir Krishna*,1 The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients. Earlier, miRNA182-5p upregulation was reported in several solid tumours and haematological malignancies. We undertook a strategy involving transient modulation and CRISPR/Cas9 (clustered regularly interspersed short palindromic repeats)-mediated knockout of the MIR182 locus in CML cells. The lineage contribution was assessed by methylcellulose colony formation assay. The transient modulation of miRNA182-5p revealed a biased phenotype. Strikingly, Δ182 cells (homozygous deletion of MIR182 locus) produced a marked shift in lineage distribution. The phenotype was rescued by ectopic expression of miRNA182-5p in Δ182 cells. A bioinformatic analysis and Hes1 modulation data suggested that Hes1 could be a putative target of miRNA182-5p. A reciprocal relationship between miRNA182-5p and Hes1 was seen in the context of TK inhibition.
    [Show full text]
  • Induction with Mitomycin C, Doxorubicin, Cisplatin And
    British Journal of Cancer (1999) 80(12), 1962–1967 © 1999 Cancer Research Campaign Article no. bjoc.1999.0627 Induction with mitomycin C, doxorubicin, cisplatin and maintenance with weekly 5-fluorouracil, leucovorin for treatment of metastatic nasopharyngeal carcinoma: a phase II study RL Hong1, TS Sheen2, JY Ko2, MM Hsu2, CC Wang1 and LL Ting3 Departments of 1Oncology, 2Otolaryngology and 3Radiation Therapy, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan Summary The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m–2, doxorubicin 40 mg m–2 and cisplatin 60 mg m–2 were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m–2 and leucovorin 30 mg m–2 for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia.
    [Show full text]
  • Mutations and Prognosis in Primary Myelofibrosis
    Leukemia (2013) 27, 1861–1869 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu ORIGINAL ARTICLE Mutations and prognosis in primary myelofibrosis AM Vannucchi1, TL Lasho2, P Guglielmelli1, F Biamonte1, A Pardanani2, A Pereira3, C Finke2, J Score4, N Gangat2, C Mannarelli1, RP Ketterling5, G Rotunno1, RA Knudson5, MC Susini1, RR Laborde5, A Spolverini1, A Pancrazzi1, L Pieri1, R Manfredini6, E Tagliafico7, R Zini6, A Jones4, K Zoi8, A Reiter9, A Duncombe10, D Pietra11, E Rumi11, F Cervantes12, G Barosi13, M Cazzola11, NCP Cross4 and A Tefferi2 Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; Po0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P ¼ 0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations.
    [Show full text]
  • The AML Guide Information for Patients and Caregivers Acute Myeloid Leukemia
    The AML Guide Information for Patients and Caregivers Acute Myeloid Leukemia Emily, AML survivor Revised 2012 Inside Front Cover A Message from Louis J. DeGennaro, PhD President and CEO of The Leukemia & Lymphoma Society The Leukemia & Lymphoma Society (LLS) wants to bring you the most up-to-date blood cancer information. We know how important it is for you to understand your treatment and support options. With this knowledge, you can work with members of your healthcare team to move forward with the hope of remission and recovery. Our vision is that one day most people who have been diagnosed with acute myeloid leukemia (AML) will be cured or will be able to manage their disease and have a good quality of life. We hope that the information in this Guide will help you along your journey. LLS is the world’s largest voluntary health organization dedicated to funding blood cancer research, advocacy and patient services. Since the first funding in 1954, LLS has invested more than $814 million in research specifically targeting blood cancers. We will continue to invest in research for cures and in programs and services that improve the quality of life for people who have AML and their families. We wish you well. Louis J. DeGennaro, PhD President and Chief Executive Officer The Leukemia & Lymphoma Society Inside This Guide 2 Introduction 3 Here to Help 6 Part 1—Understanding AML About Marrow, Blood and Blood Cells About AML Diagnosis Types of AML 11 Part 2—Treatment Choosing a Specialist Ask Your Doctor Treatment Planning About AML Treatments Relapsed or Refractory AML Stem Cell Transplantation Acute Promyelocytic Leukemia (APL) Treatment Acute Monocytic Leukemia Treatment AML Treatment in Children AML Treatment in Older Patients 24 Part 3—About Clinical Trials 25 Part 4—Side Effects and Follow-Up Care Side Effects of AML Treatment Long-Term and Late Effects Follow-up Care Tracking Your AML Tests 30 Take Care of Yourself 31 Medical Terms This LLS Guide about AML is for information only.
    [Show full text]