DOCSLIB.ORG

De Novo Megakaryoblastic Leukemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
De Novo Megakaryoblastic Leukemia HEMASPHERE-2020-0048; Total nos of Pages: 3; HEMASPHERE-2020-0048 Powered by EHA Pediatric Acute Myeloid Leukemia (AML) – Section 14 De Novo Megakaryoblastic Leukemia Thomas Mercher INSERM U1170, Team “Biology of Pediatric Leukemia”, Gustave Roussy Institute, Université Paris-Saclay, Villejuif, France Take-home messages: Genetic analyses have identified molecular subgroups with prognosis and therapeutic orientation values. Several fusion oncogenes induce acute megakaryoblastic leukemia (AMKL)-like diseases more efficiently upon expression in fetal than adult hematopoietic progenitors. AMKL result from altered transcriptional circuitries in hematopoietic stem cells. Introduction identified through classical cytogenetics.3 Alterations leading to the NUP98-KDM5a fusion are observed in 10% to 15% de De novo acute megakaryoblastic leukemia (AMKL) in the novo AMKL and a case of NUP98-BPTF∗ was reported in an fi 4,5,6 WHO 2017 classi cation corresponds to AML M7 in the former infant with refractory AMKL. Rearrangements of KMT2A – – fi French American British classi cation and represents a relatively (also referred to as MLL) leading to different fusions (eg, MLL- rare subtype of acute myeloid leukemia (AML) with blasts AF4, MLL-AF9,∗ MLL-AF10) representing in toto 7% to 17% of attributed to the megakaryocyte lineage that give rise to blood cases. 4 The NUP98 and MLL subgroups are both associated platelet production during normal hematopoiesis. AMKL affects 1,2 with aberrant expression of the homeotic HOX genes, including infants and young children more frequently than adults. The the HOXA9 gene, which has been implicated in the development cytological features of de novo AMKL are heterogeneous and and maintenance of other pediatric leukemia. The role of HOX frequently associated with low blast counts. Blasts morphologies gene alterations in pediatric AMKL development is further range from clearly megakaryocytic to completely undifferentiated, highlighted by the presence of rearrangements and overexpres- the later cases requiring immunophenotypic analyses using sion of HOX genes (eg, HOXA7, HOXA9, HOXA10, HOXB8, megakaryocyte lineage markers (eg, CD41, CD42, CD61). The HOXB9) in ∼15% of cases. The CBFA2T3-GLIS2 (a.k.a. ETO2- clinical features are also heterogenous including frequent GLIS2) fusion, resulting from a “cytogenetically-silent” inver- fi hepatosplenomegaly or myelo brosis and some cases of other sion of chromosome 16 and identified more recently by RNA fi 7,8 organ in ltrations (eg, mediastinal germ cell tumors, central sequencing, is present in 18% to 27% of de novo AMKL. nervous system, and kidney), chloroma and periostosis. Pediatric Other rarer fusions were also observed including TLS-ERG, de novo AMKL is treated with intensive chemotherapy or MN1-FLI1, BCR-ABL1, and MAP2K2-AF10. These genetic hematopoietic stem cell transplantation but remains associated 2 alterations are rarely found in adult AMKL up to date. with dismal prognosis. Importantly, about 10% of de novo pediatric AMKL present with the same genetic profile as Down’ssyndromeAMKL(ie, Current state of the art GATA1 combined with epigenetic, cohesion, and signaling mutations; described∗ by Dr Vyas below) in the context of an Over the past 20 years, cytogenetic and sequencing analyses acquired trisomy 21. 4 Other alterations remain to be identified have revealed that de novo AMKL is characterized in over 75% as 10% to 15% of patients do not show any clear causal mutation of cases by chromosomal alterations leading to the expression of to date. fusion oncogenes. The t(1;22)(p13;q13) translocation, encoding This genetics-based classification has important implications. fi the RBM15-MKL1 (a.k.a. OTT-MAL) fusion oncogene, was rst Mechanistically, it suggests different requirement for oncogenic cooperation in pediatric AMKL. Indeed, some subgroups show recurrent associations of genetic alterations. For example, The author has no conflicts of interest to disclose. NUP98-KDM5A or HOX fusions have a remarkable association Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on with RB1 inactivating mutations and MPL activating mutations, behalf of the European Hematology Association. This is an open access article respectively. On the other hand, OTT-MAL and ETO2-GLIS2 distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided fusions are rarely associated with known mutations. For the the original work is properly cited. clinical practice, these genetic alterations provide objective 9 HemaSphere (2020) 4:S2 markers for diagnosis and∗ some present value for prognosis 4 Received: 31 January 2020 / Accepted: 5 March 2020 and therapeutic orientations. While OTT-MAL was associated Educational Updates in Hematology Book | 2020; 4(S2) | 1 | HEMASPHERE-2020-0048; Total nos of Pages: 3; HEMASPHERE-2020-0048 Mercher De Novo Megakaryoblastic Leukemia with a relatively good prognosis, the NUP98-KDM5A, MLL, and induced transformation efficient upon expression in fetal hemato- ETO2-GLIS2 fusions present the poorest prognosis. This leads to poietic stem cells (HSC) but less so when expressed in adult HSC propose stem cell transplantation to ETO2-GLIS2+ AMKL and 2-gave rise to either a megakaryoblastic proliferation when patients whenever possible (Fig. 1). expressed in long-term HSC or a myeloid proliferation∗ upon The genetic heterogeneity of AMKL raises the question of the expression in committed multipotent progenitors. 14 These mechanism of transformation by AMKL oncogenes and their phenotypes are associated with different expression and activities pediatric specificities. Functional insights are emerging from of several transcription factors including GATA, ETS, and CEBP modeling approaches. A murine knock-in model of OTT-MAL factors. Importantly, expression of MLL-AF9 in fetal long-term 2 led to disease development with a low penetrance and long latency. HSC enhanced the megakaryoblastic features of leukemia while∗ The retroviral delivery of MN1-FLI1 in murine progenitors expression in adult cell led to exclusively myeloid leukemia. 14 transplanted in lethally-irradiated recipients induced bona fide These results suggest that ontogeny- and differentiation-specific leukemia with clear megakaryoblastic features.10 However, the transcriptional circuitry cooperates with pediatric fusion oncogene expression of NUP98-KDM5A, MLL fusion, NIPBL-HOXB9, and to determine the aggressiveness and phenotype of malignant cells. GATA2-HOXA9 in a similar model led to myeloid leukemia Of note, using oncogenes found in other AML subtypes, a higher without megakaryoblastic features and lacked disease development aggressiveness was also observed when expressed in LT-HSC with ETO2-GLIS2.11 Interestingly, several AMKL fusions are also compared to more committed progenitors15 or in early develop- 16,17 found in other subtypes∗ ∗ of AML (eg, MLL, NUP98, and ETO2- mental stages compared to adult. The expression of NUP98- GLIS2 fusions). 12,13, 14 These observations further raise the KDM5A in human cord blood CD34+ progenitors led to in vitro question of the bases for the association of multiple leukemic transformation and engrafted immunodeficient recipient to phenotypes by one oncogene and suggest that the cell-of-origin in recapitulate AMKL features. While proper comparison of the which these oncogenes first appear may represent an important transformation capacities at different ontogenic stages remains to determinant for human AML development and phenotypes. Using be established in human hematopoiesis; this suggests that early an inducible transgenic model, expression of ETO2-GLIS2 1- developmental stages allow for AMKL transformation. A B ( F i g u r e _ 1 ) T D $ F I G ] [ GENETIC ALTERATIONS MODEL Ontogeny Others 2% Hier HSC Unknown a 13% rchy ETO2-GLIS2 DS-like 25% 10% OTT-MAL HOX 10% Transcripon factor acvies 15% GATA1 CEBPA MLL NUP98 10% 15% Megakaryocyc Myeloid EP300-HOXA7 NUP98-KDM5A NIPBL-HOXA9 NUP98-BPTF GATA2-HOXA9 Self-renewal (ERGHI, SPILOW, …) HOXA9-ANGPT1 + Fusion GATA2-HOXA10 oncogene Signaling (KIT, …) HOXA10-AS-CD164 MLL-AF4 HOXA11-BZW2 MLL-AF9 … other mechanisms ? PLEK-HOXA11-AS MLL-AF10 C8orf76-HOXA11-AS EWSR1-HOXB8 AMKL NIPBL-HOXB9 e ce BMP2K-HOXD10 Relave incidenc 2 Age at diagnosc (years) Figure 1. Genetic and cellular bases of pediatric de novo AMKL. A: Genetic alterations observed in pediatric de novo AMKL. B: Schematic representation of some cellular and molecular bases involved in pediatric de novo AMKL development. In normal hematopoiesis, changes in the differentiation potential toward megakaryocytes (yellow) and monocytic/granulocytic myeloid lineages (blue) are observed among different hematopoietic stem cell and progenitors (hierarchy) and during the development (ontogeny). A higher megakaryocytic potential is observed during fetal hematopoiesis and is associated with differences in the activities of transcription factors, including GATA1 relatively more active in fetal hematopoiesis and CEBPA relatively more active in adult hematopoiesis. The expression of an AMKL fusion oncogene, like ETO2-GLIS2, results in more prominent deregulations of self-renewal and/or signaling proteins in a fetal vs. an adult cell context. These dependencies could represent bases for the higher incidence of AMKL (red) in early childhood. Thanks to Dr. Cécile Lopez for the development of this figure. |2| Educational Updates in Hematology Book | 2020; 4(S2) HEMASPHERE-2020-0048; Total nos
Load more

Recommended publications
  • 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]
  • 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]
  • Topologically Associating Domain Boundaries Are Commonly
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.06.443037; this version posted May 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Topologically Associating Domain Boundaries are Commonly Required for Normal Genome Function Sudha Rajderkar1, Iros Barozzi1,2,3, Yiwen Zhu1, Rong Hu4, Yanxiao Zhang4, Bin Li4, Yoko Fukuda- Yuzawa1,5, Guy Kelman1,6, Adyam Akeza1, Matthew J. Blow15, Quan Pham1, Anne N. Harrington1, Janeth Godoy1, Eman M. Meky1, Kianna von Maydell1, Catherine S. Novak1, Ingrid Plajzer-Frick1, Veena Afzal1, Stella Tran1, Michael E. Talkowski7,8,9, K. C. Kent Lloyd10,11, Bing Ren4,12,13,14, Diane E. Dickel1,*, Axel Visel1,15,16,*, Len A. Pennacchio1,15, 17,* 1 Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA. 2 Institute of Cancer Research Medical University of Vienna, Borschkegasse 8a 1090, Vienna, Austria. 3 Department of Surgery and Cancer, Imperial College London, London, UK. 4 Ludwig Institute for Cancer Research, La Jolla, CA, USA. 5 Institute of Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan. 6 The Jerusalem Center for Personalized Computational Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. 7 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. 8 Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
    [Show full text]
  • The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
    cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways.
    [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]
  • 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]
  • Acute Massive Myelofibrosis with Acute Lymphoblastic Leukemia Akut Masif Myelofibrozis Ve Akut Lenfoblastik Lösemi Birlikteliği
    204 Case Report Acute massive myelofibrosis with acute lymphoblastic leukemia Akut masif myelofibrozis ve akut lenfoblastik lösemi birlikteliği Zekai Avcı1, Barış Malbora1, Meltem Gülşan1, Feride Iffet Şahin2, Bülent Celasun3, Namık Özbek1 1Department of Pediatrics, Başkent University Faculty of Medicine, Ankara, Turkey 2Department of Medical Genetics, Başkent University Faculty of Medicine, Ankara, Turkey 3Department of Pathology, Başkent University Faculty of Medicine, Ankara, Turkey Abstract Acute myelofibrosis is characterized by pancytopenia of sudden onset, megakaryocytic hyperplasia, extensive bone mar- row fibrosis, and the absence of organomegaly. Acute myelofibrosis in patients with acute lymphoblastic leukemia is extremely rare. We report a 4-year-old boy who was diagnosed as having acute massive myelofibrosis and acute lym- phoblastic leukemia. Performing bone marrow aspiration in this patient was difficult (a “dry tap”), and the diagnosis was established by means of a bone marrow biopsy and immunohistopathologic analysis. The prognostic significance of acute myelofibrosis in patients with acute lymphoblastic leukemia is not clear. (Turk J Hematol 2009; 26: 204-6) Key words: Acute myelofibrosis, acute lymphoblastic leukemia, dry tap Received: April 9, 2008 Accepted: December 24, 2008 Özet Akut myelofibrozis ani gelişen pansitopeni, kemik iliğinde megakaryositik hiperplazi, belirgin fibrozis ve organomegali olmaması ile karakterize bir hastalıktır. Akut myelofibrozis ile akut lenfoblastik lösemi birlikteliği çok nadir görülmektedir.
    [Show full text]
  • Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation?
    Published OnlineFirst September 22, 2011; DOI: 10.1158/1541-7786.MCR-11-0382 Molecular Cancer Review Research Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation? Jenny M. Rhodes, Miranda McEwan, and Julia A. Horsfield Abstract Cohesin is a multisubunit protein complex that plays an integral role in sister chromatid cohesion, DNA repair, and meiosis. Of significance, both over- and underexpression of cohesin are associated with cancer. It is generally believed that cohesin dysregulation contributes to cancer by leading to aneuploidy or chromosome instability. For cancers with loss of cohesin function, this idea seems plausible. However, overexpression of cohesin in cancer appears to be more significant for prognosis than its loss. Increased levels of cohesin subunits correlate with poor prognosis and resistance to drug, hormone, and radiation therapies. However, if there is sufficient cohesin for sister chromatid cohesion, overexpression of cohesin subunits should not obligatorily lead to aneuploidy. This raises the possibility that excess cohesin promotes cancer by alternative mechanisms. Over the last decade, it has emerged that cohesin regulates gene transcription. Recent studies have shown that gene regulation by cohesin contributes to stem cell pluripotency and cell differentiation. Of importance, cohesin positively regulates the transcription of genes known to be dysregulated in cancer, such as Runx1, Runx3, and Myc. Furthermore, cohesin binds with estrogen receptor a throughout the genome in breast cancer cells, suggesting that it may be involved in the transcription of estrogen-responsive genes. Here, we will review evidence supporting the idea that the gene regulation func- tion of cohesin represents a previously unrecognized mechanism for the development of cancer.
    [Show full text]
  • Chronic Myelomonocytic Leukemia Early Detection, Diagnosis, and Staging Detection and Diagnosis
    cancer.org | 1.800.227.2345 Chronic Myelomonocytic Leukemia Early Detection, Diagnosis, and Staging Detection and Diagnosis Catching cancer early often allows for more treatment options. Some early cancers may have signs and symptoms that can be noticed, but that is not always the case. ● Signs and Symptoms of Chronic Myelomonocytic Leukemia ● How Is Chronic Myelomonocytic Leukemia Diagnosed? Stages and Outlook (Prognosis) After a cancer diagnosis, staging provides important information about the extent of cancer in the body and anticipated response to treatment. ● How Is Chronic Myelomonocytic Leukemia Staged? ● Survival Rates for Chronic Myelomonocytic Leukemia Questions to Ask About CMML Here are some questions you can ask your cancer care team to help you better understand your CMML diagnosis and treatment options. ● Questions to Ask Your Doctor About Chronic Myelomonocytic Leukemia 1 ____________________________________________________________________________________American Cancer Society cancer.org | 1.800.227.2345 Signs and Symptoms of Chronic Myelomonocytic Leukemia The most common sign of chronic myelomonocytic leukemia (CMML) is having too many monocytes (seen on a blood test). Having too many monocytes also causes many of the symptoms of CMML. These monocytes can settle in the spleen or liver, enlarging these organs. An enlarged spleen (called splenomegaly) can cause pain in the upper left part of the belly (abdomen). It can also cause people to notice they feel full too fast when they eat. If the liver gets too big (called hepatomegaly), it causes discomfort in the upper right part of the abdomen. Low numbers of other types of blood cells1 cause many of the signs and symptoms of CMML: ● A shortage of red blood cells (anemia) can lead to feeling very tired, with shortness of breath and pale skin.
    [Show full text]
  • Acute Myeloid Leukemia (AML)
    Acute Myeloid Leukemia (AML) AML is a blood cancer that starts in the bone marrow but moves quickly into the blood, sometimes spreading to other parts of the body. What is AML? Global Incidence Leukemia is classified based on two attributes—its speed of progression and the type of white blood cells aected. AML is the most common In 2012, the worldwide type of leukemia in adults. incidence of AML was Leukemia is described as being either acute Average age at diagnosis is estimated to be (fast growing) or chronic (slow growing), and either myelogenous (aecting the 68 350,000+ myeloid cells) or lymphocytic (aecting the lymphoid cells, or lymphocytes). Fast Growing Slow Growing Causes and Risk Factors Leukemia Leukemia Today, researchers understand a lot more Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia about what may cause AML. DNA mutations, which may result from exposure to radiation, Acute Myeloid Chronic Myeloid cancer-causing chemicals or the aging (or Myelogenous) Leukemia (or Myelogenous) Leukemia process, are commonly found in AML cells. Signs and Symptoms Prognosis At first, patients with AML often have non-specific symptoms usually associated with more common In general, prognosis for AML ailments like the flu. Often, signs and symptoms result from a shortage of normal blood cells, which patients is poor. happens when the leukemia cells crowd out the normal blood-making cells in the bone marrow. Prognosis is influenced by patient These signs and symptoms include: age, AML subtype, and other factors Estimated 5-year survival
    [Show full text]
  • Acute Myeloid Leukemia and Related L Id L Myeloid Neoplasms
    Acute myeloid leukemia and related myelidloid neoplasms: WHO 2008 brings us closer to understanding clinical behavior No conflicts of interest to disclose Steven Devine, MD The Ohio Sta te UiUnivers ity Common Presentations of AML • vague history of chronic progressive lethargy • 1/3 of patients with acute leukemia will be acutely ill with significant skin, soft tissue, or respiratory infection. • Petechiae with or without bleedinggy may be present • Leu kem ias w ith a monocy tic componen t may have gingival hypertrophy from leukemia infiltration/ extramedullary involvement (of CNS, gums, skin, other) Lab Findings in AML • The hematocrit is generally low but severe anemia is uncommon • The peripheral white blood cell count may be increased, decreased, or normal. – Approximately 35% of all AML patients will have ANC < 1,000/uL; circulating blast cells may be absent 15% of the time • Disseminated intravascular coagulation (DIC) is common, it is nearly universal in acute promyelocytic leukemia • Thrombocytopenia is frequently observed-- platelet counts <20,000/uL are common, often leads to bruising or blee ding (gums, pe tec hiae ) Basics of AML • Approximately 9,000 new cases yr in US • Incidence of AML rises with advancinggg age • The median age is 65 – Most children with leukemia have ALL (not AML) • AML is about 80% of adult acute leukemias But usuallyyy we don’t know why… • An increased incidence of AML is associated with certain conggyyenital conditions like Down syndrome, Bloom's syndrome, Fanconi's anemia • Patients with acquired
    [Show full text]
  • Cohesin Mutations in Cancer: Emerging Therapeutic Targets
    International Journal of Molecular Sciences Review Cohesin Mutations in Cancer: Emerging Therapeutic Targets Jisha Antony 1,2,*, Chue Vin Chin 1 and Julia A. Horsfield 1,2,3,* 1 Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand; [email protected] 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand 3 Genetics Otago Research Centre, University of Otago, Dunedin 9016, New Zealand * Correspondence: [email protected] (J.A.); julia.horsfi[email protected] (J.A.H.) Abstract: The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells. Keywords: cohesin; cancer; therapeutics; transcription; synthetic lethal 1. Introduction Citation: Antony, J.; Chin, C.V.; Genome sequencing of cancers has revealed mutations in new causative genes, includ- Horsfield, J.A. Cohesin Mutations in ing those in genes encoding subunits of the cohesin complex. Defects in cohesin function Cancer: Emerging Therapeutic from mutation or amplifications has opened up a new area of cancer research to which Targets.
    [Show full text]