DOCSLIB.ORG

Chronic Myeloid Leukemia in India: a Review

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chronic Myeloid Leukemia in India: a Review International Journal of Science and Healthcare Research Vol.5; Issue: 1; Jan.-March 2020 Website: www.ijshr.com Review Article ISSN: 2455-7587 Chronic Myeloid Leukemia in India: A Review Namrata Bhutani Senior Resident, Department of Biochemistry, Vardhaman Mahavir Medical College & Safdarjung Hospital, New Delhi. ABSTRACT 1973, Janet D. Rowley at the University of Chicago identified the mechanism by which Chronic myeloid leukemia (CML) is a clonal Philadelphia chromosome arises as a myeloproliferative disorder of a pluripotent stem translocation. cell. CML is the commonest adult leukaemia in Epidemiology of Chronic Myeloid India and the annual incidence ranges from 0.8– Leukemia 2.2/100,000 population in males and 0.6– 1.6/100,000 population in females in India. The Global burden of Chronic Myeloid median age of diagnosis is 38-40 years. Chronic Leukemia: myeloid leukemia is divided into three phases The incidence of CML around the based on clinical characteristics and laboratory world varies by a factor of approximately findings. CML prognostic scoring systems twofold. The lowest incidence is in Sweden stratify patients into risk groups based on patient and China (approximately 0.7 per 100,000 and disease related characteristics at diagnosis . persons), and the highest incidence is in With the introduction of the Tyrosine Kinase Switzerland and the United States Inhibitor, imatinib, the treatment and natural (approximately 1.5 per 100,000 persons). [2] history of CML has changed dramatically in CML accounts for approximately 15 recent years, with an improvement in the 5-year percent of all cases of leukemia, or survival rate from little more than 20% to over 90%.This article presents a brief review about approximately 5000 new cases per year in chronic myeloid leukemia and its therapy. the United States. The age-adjusted incidence rate in the United States is Keywords: Chronic myeloid leukemia, CML, approximately 2.0 per 100,000 persons for pluripotent stem cell, leukaemia in India. men and approximately 1.1 per 100,000 persons for women. The age-specific INTRODUCTION incidence rate for CML in the United States Chronic myeloid leukemia (CML) is increases from approximately 0.2 per a clonal myeloproliferative disorder of a 100,000 persons younger than 20 years to a pluripotent stem cell. It is characterized by rate of approximately 10.0 per 100,000 the Philadelphia (Ph) chromosome, which octogenarians per year. [3] occurs due to a balanced reciprocal Although CML occurs in children translocation between chromosome 9 and 22 and adolescents, less than 10 percent of all t(9;22)(q34.1;q11.2). It was the first cases occur in subjects between 1 and 20 malignancy that had a specific chromosomal years old. CML represents approximately 3 abnormality uniquely linked to it. This percent of all childhood leukemias. Multiple chromosomal abnormality is so named occurrences of CML in families are rare. No because it was first discovered and concordance of the disease between described in 1960 by two scientists from identical twins has been found. Analytical Philadelphia, Pennsylvania: Peter Nowell of epidemiologic evidence for a familial the University of Pennsylvania and David predisposition in CML has also not been Hungerford of the Fox Chase Cancer Center found. [4] at Temple University.(Nowell-PC). [1] In Chronic myeloid leukemia in INDIA International Journal of Science and Healthcare Research (www.ijshr.com) 6 Vol.5; Issue: 1; January-March 2020 Namrata Bhutani. Chronic myeloid leukemia in India: a review CML is the commonest adult phase, and in acute lymphoid and myeloid leukaemia in India and the annual incidence leukemias. [6] ranges from 0.8–2.2/100,000 population in Minor (m-BCR): The breakpoint in the m- males and 0.6–1.6/100,000 population in BCR region results in an e1a2 junction females in India. The median age of which is translated into a p190 BCR-ABL diagnosis is 38-40 years. This is a decade protein. Some acute lymphoblastic leukemia earlier than the median incidence in the (ALL) are induced by this protein. [7] western world. Though CML is Micro(μ-BCR): There is a third BCR-ABL predominantly a disease affecting adults, a protein: p230. It consists of more than 90% minority of patients are children and young of p160 because the breakpoint is located in adults. [5] the 3-end of the BCR gene, in the -BCR BCR-ABL Transcripts region. Its transcript contains a e19a2 The BCR/ABL fusion oncogene, the junction. The micro breakpoint position has product of the t(9;22) Philadelphia been associated mainly with a mild form of chromosome (Ph), exists in three principal CML, defined as Philadelphia chromosome- forms (P190, P210 and P230). These positive chronic neutrophilic leukaemia proteins arise from distinct breakpoints in (Phpositive CNL). [8] the BCR gene on chromosome 22. This BCR-ABL AND SIGNAL occurs due to autosplicing, which causes TRANSDUCTION [9] translocation of BCR exon 1, exons 1-12/13, The tyrosine phosphoprotein kinase or exons 1-19, respectively, to the c-ABL activity of p210BCR-ABL has been gene on chromosome 9.These different causally linked to the development of Ph- genes give rise to three distinct fusion chromosome–positive leukemia in man. proteins of molecular mass 190, 210 and p210BCR-ABL is, unlike the ABL protein 230kD. These proteins contain the same that is located principally in the nucleus, portion of the c-ABL tyrosine kinase in the located in the cytoplasm making it COOH terminus but include different accessible to a large number of interactions, amounts of Bcr sequence at the NH2 especially components of signal terminus. transduction pathways. It binds and/or Major (M-BCR): The e13a2 phosphorylates more than 20 cellular (b2a2)/e14a2 (b3a2) fusion transcripts proteins in its role as an oncoprotein. The encode for a 210-kDa protein. pathways and interactions invoked by BCR- Minor (m-BCR): The e1a2 encodes for ABL acting on mitogen-activated protein a 190-kDa protein (P190BCR-ABL). kinases are multiple and complex. [10] Micro ( -BCR): The e19a2 encodes for A subunit of phosphatidylinositol 3'- a 230-kDa protein (P230BCR-ABL) kinase (PI3K) associates with p210BCR- Major BCR-ABL (M-BCR): More than ABL; this interaction is required for the 95% Ph-positive CML patients present with proliferation of BCR-ABL–dependent cell a breakpoint in the M-BCR region. The lines and primary CML cells. most common BCR-ABL transcripts in p210BCRABL [11] regulates an RAF- CML are e13a2 (b2a2) and e14a2 (b3a2). encoded serine-threonine kinase. Two major breakpoints are found after the Downregulation of RAF expression is found 13th exon resulting in a b2a2 (e13a2) fusion to inhibit BCR-ABL–dependent growth of or after the 14th exon resulting in a b3a2 CML. [12] Cell transformation by BCR-ABL (e14a2) fusion. Both of these fusion is affected by an adaptor protein that can mRNAs are translated into p210BCR-ABL relate tyrosine kinase signals to RAS. This protein. The P210 form of BCR/ABL is involves growth factor receptor bound found in hematopoietic cells of patients with protein-2 (GRB2). p210BCR-ABL has been chronic myeloid leukemia (CML) in stable found to activate multiple alternative pathways of RAS. PI3K is constitutively International Journal of Science and Healthcare Research (www.ijshr.com) 7 Vol.5; Issue: 1; January-March 2020 Namrata Bhutani. Chronic myeloid leukemia in India: a review activated by BCR-ABL, generates inositol phosphorylates the common subunit of the lipids, and is dysregulated by the IL-3 and GMCSF receptors and JAK2. Both downregulation by BCR-ABL of ABL and BCR are also multifunctional polyinositol phosphate tumor suppressors, regulators of the GTP-binding protein such as PTEN and SHIP. [13] family Rho and the growth factor-binding The adaptor molecule CRKL is a protein GRB2, which links tyrosine kinases major in vivo substrate for p210BCR-ABL to RAS and forms a complex with BCR- as it acts to relate p210BCR-ABL to ABL and the nucleotide exchange factor Sos downstream effectors. CRKL is a linker that leads to activation of RAS. The protein that has homology to the v-crk p210BCR-ABL activates Jun kinase and oncogene product. Antibodies to CRKL can requires Jun for transformation. immunoprecipitated paxillin. Paxillin is a Reactive oxygen species are focal adhesion protein [14] that is increased in BCR-ABL–transformed cells. phosphorylated by p210BCR-ABL. The These act as a second messenger to p210BCR-ABL may be physically linked to modulate enzymes regulated by the redox paxillin by CRKL. CRKL binds to CBL, an equilibrium. An increase in these reactive oncogene product that induces B cell and oxygen products is also believed to play a myeloid leukemias in mice. The Src role in the acquisition of additional homology 3 domains of CRKL do not bind mutations through the chronic phase, to CBL, but they do bind BCR-ABL. contributing to the progression to Therefore, CRKL mediates the oncogenic accelerated phase. [16] signal of BCR-ABL to CBL. The p210BCR- ABL may, therefore, induce the formation STAGING OF CML of multimeric complexes of signaling Chronic myeloid leukemia is divided into proteins. These complexes contain paxillin three phases based on clinical characteristics and talin and explain some of the adhesive and laboratory findings. In the absence of defects of CML cells. intervention, CML typically begins in the Hef2 also binds to CRKL in leukemic chronic phase and over the course of several tissues of p190BCR-ABL transgenic mice. years progresses to an accelerated phase and Hef2 is involved in the integrin signaling ultimately to a blast crisis. pathway [15] and encodes a protein that Chronic phase: Approximately 85% of accelerates GTP hydrolysis of RAS-encoded patients with CML are in the chronic proteins and neurofibromin.
Load more

Recommended publications
  • Chronic Myelogenous Leukemia
    Chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also referred to as chronic chronic myelocytic leukemia , may be a cancer of the white blood cells. It’s a sort of leukemia characterized by the increased and unregulated growth of myeloid cells within the bone marrow and therefore the accumulation of those cells within the blood. CML may be a clonal bone marrow somatic cell disorder during which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found. it's a kind of myeloproliferative neoplasm related to a characteristic chromosomal translocation called the Philadelphia chromosome. CML is essentially treated with targeted drugs called tyrosine-kinase inhibitors (TKIs) which have led to dramatically improved long- term survival rates since 2001. These drugs have revolutionized treatment of this disease and permit most patients to possess an honest quality of life in comparison to the previous chemotherapy drugs. In Western countries, CML accounts for 15–25% of all adult leukemias and 14% of leukemias overall (including the pediatric population, where CML is a smaller amount common). Signs and symptoms The way CML presents depends on the stage of the disease at diagnosis because it has been known to skip stages in some cases. Most patients (~90%) are diagnosed during the chronic stage which is most frequently asymptomatic. In these cases it's going to be diagnosed incidentally with an elevated white blood corpuscle calculate a routine laboratory test. It also can present with symptoms indicative of hepatosplenomegaly and therefore the resulting upper quadrant pain this causes. The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss.
    [Show full text]
  • Gleevec's Glory Days
    Diabetes Detectives || $$$ to Databases || Anthrax 101 || Fighting Parasites in Bangladesh DECEMBER 2001 Gleevec’s Glory Days The Long Journey of a Celebrated Anticancer Drug FEATURES Gleevec’s Glory Days Mirpur’s Children 10 22 An apparent overnight success, this new A slum in Bangladesh yields clues about leukemia drug has decades of research behind it. immunity, infection and an illness that afflicts By Jill Waalen millions worldwide. By David Jarmul 16 Confronting Diabetes From All Angles 26 Scientific Outliers To combat this growing epidemic, researchers are hunting for genes, exploring cell-signaling How teachers and students in rural America pathways and looking at obesityÕs role. can learn good science. By Karen Hopkin By Mitch Leslie 16 In Starr County, Texas, an alarming 2,500 Mexican- American residents have type 2 diabetes. These women, at the Starr County Health Studies Office, undergo regular monitoring of their disease, which has strong genetic and evironmental components. DEPARTMENTS 2 NOTA BENE 30 HANDS ON Howard Hughes Medical Institute Bulletin ulletin Building Interest in the December 2001 || Volume 14 Number 5 3 PRESIDENT’S LETTER Human Body HHMI TRUSTEES Biomedical Research in a James A. Baker, III, Esq. Changed World Senior Partner, Baker & Botts NEWS AND NOTES Alexander G. Bearn, M.D. Executive Officer, American Philosophical Society 32 To Think Like a Scientist Adjunct Professor, The Rockefeller University UP FRONT Professor Emeritus of Medicine, Cornell University Medical College Frank William Gay 4 Mouse Model Closely 33 Undergraduate Taps Into Former President and Chief Executive Officer, summa Corporation James H. Gilliam, Jr., Esq. Mimics Human Cancer Tomato Communication Former Executive Vice President and General Counsel, Beneficial Corporation 6 Database Science Forcing New Hanna H.
    [Show full text]
  • Chronic Myeloid Leukemia: a Model Disease of the Past, Present and Future
    cells Review Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future Valentina R. Minciacchi 1,† , Rahul Kumar 1,† and Daniela S. Krause 1,2,3,4,5,* 1 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt am Main, Germany; [email protected] (V.R.M.); [email protected] (R.K.) 2 German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany 3 German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany 4 Frankfurt Cancer Institute, 60596 Frankfurt, Germany 5 Faculty of Medicine, Medical Clinic II, Johann Wolfgang Goethe University, 60596 Frankfurt, Germany * Correspondence: [email protected]; Tel.: +49-69-63395-500; Fax: +49-69-63395-519 † These authors contributed equally. Abstract: Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Be- ginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage. Keywords: chronic myeloid leukemia; history; targeted therapy; metabolism; bone marrow microen- vironment; combination therapies 1. The History of Chronic Myeloid Leukemia Citation: Minciacchi, V.R.; Kumar, R.; Krause, D.S. Chronic Myeloid The first descriptions of chronic myeloid leukemia (CML), or as it was called at the Leukemia: A Model Disease of the beginning, chronic granulocytic leukemia, can be dated back to 1845.
    [Show full text]
  • Nature Medicine Essay
    COMMENTARY Clinical Medical Research Award Cancer genetics, cytogenetics—defining the enemy within Suggestions of a significant relationship nantly inherited breast and colon cancers between chromosome abnormalities and PETER NOWELL, JANET ROWLEY had been described, as had hereditary tumor development came first from sev- & ALFRED KNUDSON retinoblastoma and neurofibromatosis. eral German pathologists in the late nine- The relationship between rare heritable teenth century1. It was, however, the biologist Theodor Boveri, cancers and common nonhereditary cancers was puzzling and who worked with sea urchins, not tumors, who first posited sev- mostly beyond investigation in the absence of the ability to eral hypotheses (subsequently proved correct) on the impor- map and clone genes. Meanwhile, there could be only specula- tance of somatic genetic changes in tumor development2. tion about the determinants and mechanisms of penetrance in Boveri observed developmental defects in sea urchins with mi- heterozygous carriers of mutant genes. Early studies of cancer totic abnormalities and suggested that mammalian tumors inheritance in mice pointed towards multigenic determination might be similarly initiated by aneuploid chromosome comple- of carcinogenesis and away from strongly predisposing single ments. Remarkably, he also suggested the importance of genetic genes. instability in tumor cell populations, the possible unicellular origin of tumors and the significance of specific chromosomal or submicroscopic changes. Unfortunately these hypotheses preceded the techniques required to test them and so Boveri’s concepts lay dormant for several decades. In the 1930s and 1940s a few studies in both experimental and human tumors did suggest that chromosome numbers were usually abnormal in neoplastic cells and the concept of a ‘stem- line’ or clonal nature of tumors, with acquisition of additional genetic changes over time, was explored, primarily in trans- plantable rodent tumors1.
    [Show full text]
  • To Cancer Growth Advantage, the Age-Specific Incidence (I) Would Be I = Kt R–1
    PERSPECTIVES 6. Borst, M. J. & Ingold, J. A. Metastatic patterns of invasive 18. Kononen, J. et al. Tissue microarrays for high-throughput cancer in patients with xeroderma pigmen- lobular versus invasive ductal carcinoma of the breast. molecular profiling of tumor specimens. Nature Med. 4, Surgery 114, 637–641 (1993). 844–847 (1998). tosum, a condition to which Boveri drew 7. Elledge, R. M. et al. HER2 expression and response to 19. Camp, R. L. et al. Validation of tissue microarray attention1, was shown to be a consequence tamoxifen in estrogen receptor-positive breast cancer: a technology in breast carcinoma. Lab. Invest. 80, Southwest Oncology Group Study. Clin. Cancer Res. 4, 1943–1949 (2000). of somatic mutations in the presence of a 7–12 (1998). 20. Khan, J. et al. Classification and diagnostic prediction of hereditary defect in the repair of ultraviolet- 8. Elston, C. W. et al. Causes of inconsistency in diagnosing cancers using gene expression profiling and artificial 7 and classifying intraductal proliferations of the breast. Eur. neural networks. Nature Med. 7, 673–679 (2001). light-induced damage to DNA . Chemical J. Cancer 36, 1769–1772 (2000). 21. Hedenfalk, I. et al. Gene-expression profiles in hereditary carcinogenesis also fitted into the mutation- 9. Jones, C. et al. Comparative genomic hybridization breast cancer. N. Engl. J. Med. 344, 539–548 (2001). analysis of myoepithelial carcinoma of the breast. Lab. al concept of cancer with the observations Invest. 80, 831–836 (2000). of ‘initiation’ by carcinogens and of ‘promo- 10. Jones, C. et al. CGH analysis of ductal carcinoma of the Online links 8 breast with basaloid/myoepithelial cell differentiation.
    [Show full text]
  • The History of Myeloproliferative Disorders: Before and After Dameshek
    Leukemia (2008) 22, 3–13 & 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00 www.nature.com/leu SPOTLIGHT REVIEW The history of myeloproliferative disorders: before and after Dameshek A Tefferi Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA In 1951, William Dameshek described the concept of ‘myelo- in these disorders; we now believe this to be mutant tyrosine proliferative disorders (MPDs)’ by grouping together chronic kinases, for the most part.9–15 The history of MPDs antedates myelogenous leukemia (CML), polycythemia vera (PV), essen- Dameshek by more than a century and substantial progress has tial thrombocythemia (ET), primary myelofibrosis (PMF) and been made since his time, including the discoveries of BCR– erythroleukemia; he reasoned that a self-perpetuating trilineage 9,16–18 19 10–13 myeloproliferation underlined their pathogenesis. Pre-Dame- ABL, imatinib and JAK2V617F. Herein, I summa- shek luminaries who laid the foundation for this unifying rize some of the key events in the history of the classic MPDs concept include Bennett, Virchow, Heuck, Vaquez, Osler, before and after Dameshek. Di Guglielmo and Epstein. In 1960, Nowell and Hungerford discovered the Philadelphia (Ph) chromosome in CML. In 1967, Fialkow and colleagues used X-linked polymorphisms to establish CML as a clonal stem cell disease. Also in 1967, the The early times: humors, plethora and bloodletting PV Study Group was summoned by Louis Wasserman to study the natural history of PV and conduct large-scale clinical trials. According to Hippocrates, The Father of Medicine, (460–370 In 1972, Janet Rowley deciphered the Ph chromosome as a BC) and Galen, the most prominent physician after Hippocrates, reciprocal translocation between chromosomes 9 and 22, thus (129–200 AD), blood was recognized as one of the four ‘humors’ paving the way for its subsequent characterization as an oncogenic BCR–ABL mutation.
    [Show full text]
  • For Treating Chronic Myeloid Leukemia
    Age Disparity in the Dissemination of Imatinib Mesylate (Gleevec) for Treating Chronic Myeloid Leukemia Chuck Wiggins, Ph.D. Director and Principal Investigator New Mexico Tumor Registry North American Association of Central Cancer Registries June 23, 2011 University of New Mexico – Health Sciences Center Collaborators • Linda C. Harlan, Ph.D. –National Cancer Institute • Harold E. Nelson, M.A. –New Mexico Tumor Registry • Jennifer Stevens, B.A. – IMS, Incorporated • Cheryl L. Willman, M.D. –University of New Mexico • Edward N. Libby, M.D. –University of New Mexico • Robert A. Hromas, M.D. –University of New Mexico Funding • National Cancer Institute • Leukemia and Lymphoma Society Chronic Myeloid Leukemia • Myeloproliferative disorder • Philadelphia chromosome • Course of disease: Chronic phase Accelerated phase Blast phase • Annual number of new cases: United States – 4,830 • Annual number of deaths: United States – 450 1960 – Identification of the Philadelphia Chromosome Peter Nowell University of Pennsylvania School of Medicine David Hungerford Fox Chase Cancer Center 1972 – Philadelphia Chromosome results from translocation Janet Rowley University of Chicago t(9,22;q34,q11) 1982 –Abl gene translocated from 9q to 22q Annelies de Klein and colleagues –Erasmus University Protein Tyrosine Kinases • Enzymes –agents of change • Modulate a number of cellular events: Differentiation Growth Metabolism Apoptosis The BCR‐ABL gene produces an abnormal tyrosine kinase protein that results in the disordered myelopoiesis found in Chronic Myeloid Leukemia Imatinib Mesylate (GleevecTM, Novartis, Basel, Switzerland) • Tyrosine Kinase Inhibitor • FDA approved in May, 2001 • Highly active against Chronic Myeloid Leukemia and Gastro‐Intestinal Stromal Tumors (GIST) Late 1990’s to Mid 2000’s: Clinical Trials for Imatinib Brian Druker Data Sources 1.
    [Show full text]