Molecular Hematology, Second Edition

348 Pages·9.578 MB·English

Molecular Hematology
Molecular
Hematology
SECOND EDITION
Edited by
Drew Provan
MD FRCP FRCPath
Senior Lecturer in Haematology
Department of Haematology
Barts and The Royal London School of Medicine and Dentistry
Whitechapel
London
UK
John G Gribben
MD DSc FRCP FRCPath
Associate Professor
Division of Medical Oncology
Dana-Farber Cancer Institute
Department of Medicine
Brigham and Women's Hospital
Harvard Medical School
Boston
USA
© 2000, 2005 by Blackwell Publishing Ltd
Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA
Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK
Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia
The right of the Authors to be identified as the Authors of this Work has been asserted in accordance with the
Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in
any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by
the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
First published 2000
Second edition 2005
Library of Congress Cataloging-in-Publication Data
Molecular haematology / edited by Drew Provan, John Gribben.
-- 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 1-4051-1255-7
1. Blood--Diseases--Molecular aspects. I. Provan, Andrew.
II. Gribben, John. III. Title: Molecular hematology,
[DNLM: 1. Hematologic Diseases. 2. Molecular Biology.
WH 120 M7187 2004]
RC636.M576 2004
616.1’5--dc22

2004000858
ISBN 1-4051-1255-7
A catalogue record for this title is available from the British Library
Set in 10/12 pt Minion by Sparks, Oxford – www.sparks.co.uk
Printed and bound in India by Gopsons Papers Ltd., NOIDA
Commissioning Editor: Maria Khan
Managing Editor: Rupal Malde
Production Editor: Fiona Pattison
Production Controller: Kate Charman
For further information on Blackwell Publishing, visit our website:
http://www.blackwellpublishing.com
The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and
which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices.
Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental
accreditation standards.
Dedication
We would like to dedicate this book to our families, especially Val, Fraser and Peter, who provided constant encouragement and
support throughout the project.
v
Contents
List of Contributors, ix 12 The molecular basis of anemia, 125
Foreword, xiii Lucio Luzzatto & Anastasios Karadimitris
Preface, xv
13 The molecular basis of iron metabolism, 150
Abbreviations, xvii
Nancy C Andrews
14 Hemoglobinopathies due to structural mutations, 159
1 Beginnings: the molecular pathology of hemoglobin, 1
Ronald L Nagel
David Weatherall
15 Molecular coagulation and thrombophilia, 173
2 Molecular cytogenetics, 18
Björn Dahlbäck & Andreas Hillarp
Debra M Lillington, Silvana Debernardi & Bryan D Young
16 The molecular basis of hemophilia, 184
3 Stem cells, 25
Paul L F Giangrande
Eyal C Attar & David T Scadden
17 The molecular basis of von Willebrand disease, 199
4 The genetics of acute myeloid leukemias, 41
Luciano Baronciani & Pier Mannuccio Mannucci
D Gary Gilliland
18 Platelet disorders, 210
5 Secondary myelodysplasia/acute myelogenous
Katherine A Downes & Keith R McCrae
leukemia—assessment of risk, 47
D Gary Gilliland & John G Gribben 19 The molecular basis of blood cell alloantigens, 225
Willem H Ouwehand & Cristina Navarrete
6 Detection of minimal residual disease in hematological
malignancies, 53 20 Functions of blood group antigens, 241
Drew Provan & John G Gribben John R Pawloski & Marilyn J Telen
7 Chronic myeloid leukemia, 72 21 Autoimmune hematological disorders, 251
Brian J Druker Drew Provan, James B Bussel & Adrian C Newland
8 Myelodysplastic syndromes, 82 22 Hematopoietic growth factors, 267
Jaqueline Boultwood & James S Wainscoat Graham Molineux
9 Myeloproliferative disorders, 90 23 Molecular therapeutics in hematology, 280
Anthony J Bench, George S Vassiliou, Brian J P Huntly & A Keith Stewart & Jeffrey A Medin
Anthony R Green
24 Gene expression profiling in the study of lymphoid
10 Lymphoid neoplasms, 105 malignancies, 298
Anthony G Letai & John G Gribben Ulf Klein & Riccardo Dalla-Favera
11 The molecular biology of multiple myeloma, 115 Appendices, 307
P Leif Bergsagel Index, 313
Color plate, facing p. 174
vii
List of contributors
Nancy C Andrews MD PhD Björn Dahlbäck MD PhD
Associate Investigator, Howard Hughes Medical Institute, Professor of Blood Coagulation Research, Department of
Associate Professor, Harvard Medical School, and Associate Clinical Chemistry, University of Lund, University Hospital,
in Medicine, Children’s Hospital Boston, 300 Longwood Malmo S-20502, Sweden
Avenue, Boston, MA 02115, USA
Riccardo Dalla-Favera MD
Eyal C Attar MD Director, Institute for Cancer Genetics, Columbia University,
Instructor in Medicine, Harvard Medical School, 1150 St Nicholas Avenue, New York, NY 10032, USA
Massachusetts General Hospital, Boston, MA 02129, USA
Silvana Debernardi PhD
Luciano Baronciani PhD Scientist, Cancer Research UK, Medical Oncology Unit,
Research Assistant, Angelo Bianchi Bonomi Hemophilia and Barts and The London, Queen Mary's School of Medicine
Thrombosis Center, IRCCS Maggiore Hospital, 20122 Milan, and Dentistry, Charterhouse Square, London EC1M 6BQ,
Italy UK
Anthony J Bench MA PhD Katherine A Downes MD
Senior Scientist, Department of Haematology, Assistant Professor of Pathology, Department of Pathology,
Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, Case Western Reserve University School of Medicine/
UK University Hospitals of Cleveland, 11000 Euclid Avenue
Humphrey 5611, PTH 5077, Cleveland, OH 44106, USA,
P Leif Bergsagel MD FRCP(C) and Director of Coagulation, Associate Director of Blood
Associate Professor of Medicine, Division of Hematology/ Banking/Transfusion Medicine, University Hospitals of
Oncology, Weill Medical College of Cornell University, 1300 Cleveland, Cleveland, OH, USA
York Avenue, New York, NY 10021, USA
Brian J Druker MD
Jaqueline Boultwood Investigator, Howard Hughes Medical Institute and
University Research Lecturer and Co-Director of Leukaemia JELD-WEN Chair of Leukemia Research, Department of
Research Fund Molecular Haematology Unit, Nuffield Hematology/Medical Oncology, Oregon Health Sciences
Department of Clinical Laboratory Sciences, John Radcliffe University Cancer Institute, L592, 3181 SW Sam Jackson
Hospital, Oxford OX3 9DU, UK Park Road, Portland, OR 97201-3011, USA
James B Bussel MD Paul L F Giangrande BSc MD FRCP FRCPath
Professor of Pediatrics, Division of Pediatrics, New York FRCPCH
Presbyterian Hospital, Weill Cornell Medical Center, 525 E. Consultant Haematologist and Director, Oxford
68th Street, Payson 609, New York, NY 10021, USA Haemophilia Centre and Thrombosis Unit, Churchill
Hospital, Oxford OX3 7LJ, UK
ix
x List of contributors
D Gary Gilliland MD PhD Lucio Luzzatto MD
Professor of Medicine, Howard Hughes Medical Institute, Scientific Director, National Institute for Cancer Research,
Brigham and Women’s Hospital, Dana-Farber Cancer Istituto Scientifico Tumori, Largo, Rosanna Benzi, 10, 16132
Institute, Harvard Medical School, Boston, MA 02115, USA Genova, Italy
Anthony R Green PhD FRCP FRCPath Pier Mannuccio Mannucci MD
Wellcome Senior Fellow and Honorary Consultant Professor and Chairman of Internal Medicine, Angelo
Haematologist, Department of Haematology, University of Bianchi Bonomi Hemophilia and Thrombosis Center,
Cambridge, MRC Centre, Hills Road, Cambridge CB2 2QH, IRCCS Maggiore Hospital, 20122 Milan, Italy
UK
Keith R McCrae MD
John G Gribben MD DSc FRCP FRCPath Associate Professor of Medicine Hematology-Oncology,
Associate Professor, Division of Medical Oncology, Dana- BRB 3, Case Western Reserve University, School of Medicine,
Farber Cancer Institute, Department of Medicine, Brigham 10900 Euclid Avenue, Cleveland, OH 44106-4937, USA
and Women’s Hospital, Harvard Medical School, Boston,
MA 02115, USA Jeffrey A Medin PhD
Associate Professor, Department of Medical Biophysics,
Andreas Hillarp PhD University of Toronto, Ontario Cancer Institute, Princess
Associate Professor and Hospital Chemist, Department of Margaret Hospital, 610 University Avenue, Rm 7-411,
Clinical Chemistry, University of Lund, University Hospital, Toronto, Ontario M5G 2M9, Canada
Malmo S-20502, Sweden
Graham Molineux PhD
Brian J P Huntley MB ChB MRCP DipRCPath Amgen Inc., Mailstop 15-2-A, One Amgen Center Drive,
Clinical Research Fellow, Department of Haematology, Thousand Oaks, CA 91320, USA
University of Cambridge, MRC Centre, Hills Road,
Cambridge CB2 2QH, UK Ronald L Nagel MD
Irving D. Karpas Professor of Medicine, Head, Division
Anastasios Karadimitris PhD MRCP MRCPath of Hematology, Albert Einstein College of Medicine, The
Senior Lecturer and Honorary Consultant Haematologist, Bronx, New York, NY 10461, USA
Leukaemia Research Fund Bennett Senior Fellow,
Department of Haematology, Imperial College London, Cristina Navarrete PhD
Hammersmith Hospital Campus, Du Cane Road, London Head of Histocompatibility and Immunogenetics, National
W12 0NN, UK Blood Service, Colindale Avenue, London NW9 5BG, UK
Ulf Klein PhD Adrian C Newland MA FRCP FRCPath
Associate Research Scientist, Columbia University, Institute Professor of Haematology, Department of Haematology,
of Cancer Genetics, Russ Berrie Pavillion, 1150 St Nicholas Barts and The London, Queen Mary's School of Medicine
Avenue, New York, NY 10032, USA and Dentistry, Whitechapel, London E1 1BB, UK
Anthony G Letai MD PhD Willem H Ouwehand MD PhD
Assistant Professor in Medicine, Harvard Medical School, Lecturer in Haematology, Division of Transfusion Medicine,
Smith 758, Dana-Farber Cancer Institute, 1 Jimmy Fund Department of Haematology, University of Cambridge,
Way, Boston, MA 02115, USA Cambridge CB2 2PT, UK
Debra M Lillington BSc John R Pawloski MD PhD
Head of Cytogenetics, ICRF Medical Oncology Laboratory, Assistant Professor of Medicine, Division of Hematology,
Barts and The London, Queen Mary's School of Medicine and Department of Medicine, Duke University, Durham,
Dentistry, Charterhouse Square, London EC1M 6BQ, UK NC 27710, USA
List of contributors xi
Drew Provan MD FRCP FRCPath George S Vassiliou MRCP(UK) DipRCPath BSc
Senior Lecturer in Haematology, Department of Hons (Lond)
Haematology, Barts and The London, Queen Mary's School Leukaemia Research Fund Clinical Research Fellow/Hon.
of Medicine and Dentistry, Whitechapel, London E1 1BB, UK Specialist Registrar, Department of Haematology, University
of Cambridge, Cambridge Institute for Medical Research,
David T Scadden MD Hills Road, Cambridge CB2 2XY, UK
Professor of Medicine, Harvard Medical School, AIDS
Research Centre, Massachusetts General Hospital, 149, 13th James S Wainscoat FRCP FRCPath
Street, CNY 5212, Charleston, Boston, MA 02129-2020, USA Consultant Haematologist, Department of Haematology,
John Radcliffe Hospital, Marston, Oxford OX3 9DU, UK
A Keith Stewart MD FRCP(C)
Associate Professor, Department of Medical Oncology/ David Weatherall FRS
Hematology, Princess Margaret Hospital, 610 University Regius Professor of Medicine, University of Oxford,
Avenue, Toronto, Ontario M5G 2M9, Canada Institute of Molecular Medicine, John Radcliffe Hospital,
Headington, Oxford OX3 9DS, UK
Marilyn J Telen MD
Wellcome Professor of Hematology and Director, Duke- Bryan D Young BSc PhD
UNC Comprehensive Sickle Center, Box 2615 Duke Head and Professor of ICRF Medical Oncology Laboratory,
University Medical Center, Durham, NC 27710, USA Barts and The London, Queen Mary's School of Medicine and
Dentistry, Charterhouse Square, London EC1M 6BQ, UK
Foreword
In 1968, after a quest lasting 30 years, X-ray analysis of crystal- the design of anti-sickling drugs, but after an effort lasting
line horse hemoglobin at last reached the stage when I could 10 years, we realized that we were running up against a brick
build a model of its atomic structure. The amino acid se- wall. Luckily, the work was not entirely wasted, because we
quences of human globin are largely homologous to those of found a series of compounds that lower the oxygen affinity of
horse globin, which made me confident that their structures hemoglobin and we realized that this might be clinically use-
are the same. By then, the amino acid substitutions responsi- ful. One of those compounds, designed by DJ Abraham at the
ble for many abnormal human hemoglobins had been deter- University of Virginia in Richmond, is now entering phase 3
mined. The world authority on them was the late Hermann clinical trials. On the other hand, our failure to find a drug
Lehmann, Professor of Clinical Biochemistry at the Univer- against sickle cell anemia, even when its cause was known in
sity of Cambridge, who worked in the hospital just across the atomic detail, made me realize the extreme difficulty of find-
road from our Laboratory of Molecular Biology. I asked him ing drugs to correct a malfunction of a protein that is caused
to come over to see if there was any correlation between the by a single amino acid substitution. Most thalassemias are
symptoms caused by the different amino acids substituted in due not to amino acid substitutions, but to either complete
the abnormal hemoglobin and their positions in the atomic or partial failure to synthesize α- or β-globin chains. Weath-
model. The day we spent going through them proved one of erall’s chapter shows that, at the genetic level, there may be
the most exciting in our scientific lives. We found hemoglobin literally hundreds of different genetic lesions responsible for
to be insensitive to replacements of most amino acid residues that failure. Correction of such lesions is now the subject of
on its surface, with the notable exception of sickle cell he- intensive work in many laboratories.
moglobin. On the other hand, we found the molecule to be Early in the next century, the human genome will be com-
extremely sensitive to even quite small alterations of internal plete. It will reveal the amino acid sequences of all the 100000
non-polar contacts, especially those near the hemes. Replace- or so different proteins of which we are made. Many of these
ments at the contact between the α and β subunits affected proteins are still unknown. To discover their functions, the
respiratory function. next project now under discussion is a billion dollar effort
In sickle cell hemoglobin an external glutamate was re- to determine the structures of all the thousands of unknown
placed by a valine. We wrote: ‘A non-polar instead at a polar proteins within 10 years. By then we shall know the identity
residue at a surface position would suffice to make each mol- of the proteins responsible for most of the several thousand
ecule adhere to a complementary site at a neighbouring one, different genetic diseases. Will this lead to effective treat-
that site being created by the conformational change from oxy ment or will medical geneticists be in the same position as
to deoxy haemoglobin’. This was soon proved to be correct. doctors were early in this century when the famous physician
We published our findings under the title: ‘The Molecular Sir William Osler confined their task to the establishment of
Pathology of Human Haemoglobin’. Our paper marked a diagnoses? Shall we know the cause of every genetic disease
turning point because it was the first time that the symp- without a cure?
toms of diseases could be interpreted in terms of changes Our only hope lies in somatic gene therapy. AK Stewart’s
in the atomic structure of the affected protein. In the years chapter on Molecular Therapeutics describes the many in-
that followed, the structure of the contact between the valine genious methods now under development. So far, none of
of one molecule of sickle cell hemoglobin and that of the these has produced lasting effects, apparently because the
complementary site of its neighbor became known in some transferred genes are not integrated into the mammalian ge-
detail. At a meeting at Arden House near Washington in 1980, nome, but a large literature already grown up bears testimony
several colleagues and I decided to use this knowledge for to the great efforts now underway to overcome this problem.
xiii
xiv Foreword
My much-loved teacher William Lawrence Bragg used to say
‘If you go on hammering away at a problem, eventually it seems
to get tired, lies down and lets you catch it.’ Let us hope that
somatic gene therapy will soon get tired.
M.F. Perutz
Cambridge
Perutz MF, Lehmann H. (1968) Molecular pathology of human haemo-
globin. Nature, 219, 902–909.
Perutz MF, Muirhead H, Cox JM, Goaman LCG. (1968) Three-dimen-
sional Fourier synthesis of horse oxyhaemoglobin at 2.8Å resolution:
the atomic model. Nature, 219, 131–139.