Przewlekła białaczka szpikowa – Etiologia i przyczyny

Przewlekła białaczka szpikowa
Etiologia i przyczyny

Przewlekła białaczka szpikowa (CML) jest nowotworem hematologicznym charakteryzującym się niekontrolowaną proliferacją komórek linii granulocytarnej, spowodowaną obecnością chromosomu Philadelphia (Ph) w ponad 90-95% przypadków. Translokacja t(9;22)(q34;q11.2) prowadzi do powstania genu fuzyjnego BCR-ABL1, kodującego konstytutywnie aktywną kinazę tyrozynową, która zaburza szlaki sygnałowe komórkowe, zwiększając proliferację, zmniejszając apoptozę i powodując niestabilność genomową. Postęp choroby wiąże się z dodatkowymi aberracjami genetycznymi, takimi jak trisomia 8, izochromosom 17 czy duplikacja chromosomu Philadelphia, które mogą indukować oporność na inhibitory kinazy tyrozynowej (TKI). CML najczęściej diagnozuje się u osób w wieku 40-60 lat, z przewagą mężczyzn, a głównym udokumentowanym czynnikiem ryzyka jest ekspozycja na wysokie dawki promieniowania jonizującego. Inne potencjalne czynniki ryzyka to długotrwała ekspozycja na benzen i chemikalia przemysłowe, podczas gdy dziedziczność, palenie tytoniu, dieta i infekcje nie wykazują istotnego wpływu na rozwój choroby.

Etiologia przewlekłej białaczki szpikowej

Chromosom Philadelphia i gen BCR-ABL
Dodatkowe zmiany genetyczne
Czynniki ryzyka przewlekłej białaczki szpikowej
Czynniki niezwiązane z rozwojem CML
Inicjujące czynniki mutacji BCR-ABL
Modele doświadczalne CML

Podsumowanie etiologii CML

Kolejne rozdziały

Etiologia przewlekłej białaczki szpikowej

Przewlekła białaczka szpikowa (CML, chronic myeloid leukemia) jest nowotworem krwi i szpiku kostnego charakteryzującym się niekontrolowanym wzrostem i nadprodukcją komórek linii granulocytarnej. Choroba ta wynika z konkretnych zmian genetycznych, które powstają w komórkach macierzystych szpiku kostnego.¹² Zrozumienie etiologii CML jest kluczowe dla właściwego postępowania terapeutycznego.

Chromosom Philadelphia i gen BCR-ABL

U ponad 90-95% pacjentów z CML występuje charakterystyczna aberracja chromosomowa znana jako chromosom Philadelphia (Ph).¹² Chromosom ten powstaje w wyniku wzajemnej translokacji pomiędzy chromosomami 9 i 22, zapisywanej jako t(9;22)(q34;q11.2).¹² W procesie tym fragment chromosomu 9 zawierający protoonkogen ABL (Abelson leukemia virus) odłącza się i łączy z fragmentem chromosomu 22 w regionie BCR (breakpoint cluster region).¹²

Ta translokacja prowadzi do utworzenia nowego genu fuzyjnego BCR-ABL1, który jest odpowiedzialny za produkcję nieprawidłowego białka – kinazy tyrozynowej BCR-ABL.¹² Białko to charakteryzuje się konstytutywną (stałą) aktywnością kinazy tyrozynowej, co prowadzi do zaburzenia szlaków sygnałowych w komórce i w konsekwencji do niekontrolowanej proliferacji komórek.¹²

Kinaza tyrozynowa BCR-ABL aktywuje liczne szlaki przekazywania sygnału w komórce, co prowadzi do:¹²

Zwiększonej proliferacji komórek białaczkowych
Zmniejszonej apoptozy (programowanej śmierci komórkowej)
Zaburzenia dojrzewania komórek
Zwiększonej niestabilności genomowej

¹²

Centralna rola białka BCR-ABL w patogenezie CML została potwierdzona skutecznością inhibitorów kinazy tyrozynowej (TKI), które blokują aktywność tego białka i mogą powodować całkowitą remisję choroby.¹²

Dodatkowe zmiany genetyczne

Wraz z progresją choroby z fazy przewlekłej do fazy akceleracji i przełomu blastycznego, w komórkach białaczkowych mogą pojawić się dodatkowe zmiany genetyczne.¹² Najczęstsze z nich to:

Dodatkowa kopia chromosomu 8 (trisomia 8)
Nieprawidłowości chromosomu 17 znane jako izochromosom 17
Dodatkowa kopia (duplikacja) chromosomu Philadelphia
Inne mutacje punktowe w domenie kinazowej BCR-ABL

¹²

Te dodatkowe mutacje mogą prowadzić do dalszej deregulacji cyklu komórkowego i niekontrolowanej proliferacji, a także do oporności na leczenie inhibitorami kinazy tyrozynowej.¹²

Czynniki ryzyka przewlekłej białaczki szpikowej

W przeciwieństwie do niektórych innych nowotworów, w przypadku CML zidentyfikowano stosunkowo niewiele wyraźnych czynników ryzyka.¹² Do głównych należą:

Wiek

Ryzyko zachorowania na CML wzrasta wraz z wiekiem. Choroba najczęściej występuje u osób w wieku 40-60 lat, przy czym ponad połowa przypadków diagnozowana jest u osób powyżej 60. roku życia.¹² CML rzadko występuje u dzieci i nastolatków.¹

Ekspozycja na promieniowanie jonizujące

Najbardziej udokumentowanym czynnikiem ryzyka CML jest ekspozycja na wysokie dawki promieniowania jonizującego.¹² Zwiększoną częstość występowania CML zaobserwowano u:

Osób, które przeżyły wybuchy bomb atomowych w Hiroszimie i Nagasaki
Pracowników likwidujących skutki awarii elektrowni jądrowej w Czarnobylu
Pacjentów poddanych wcześniej radioterapii z powodu innych nowotworów (np. chłoniaka Hodgkina czy raka tarczycy)

¹²³

Należy jednak podkreślić, że większość pacjentów z CML nie miała w wywiadzie narażenia na wysokie dawki promieniowania.¹

Płeć

CML występuje nieco częściej u mężczyzn niż u kobiet.¹² Przyczyna tej różnicy nie jest w pełni wyjaśniona.¹

Ekspozycja na czynniki chemiczne

Długotrwała ekspozycja na benzen i inne chemikalia przemysłowe może zwiększać ryzyko rozwoju CML, chociaż związek ten jest mniej udokumentowany niż w przypadku promieniowania.¹²³ Badania wykazały, że pracownicy narażeni na ekspozycję benzenu, pestycydów i innych chemikaliów mogą mieć podwyższone ryzyko zachorowania na CML.¹

Czynniki niezwiązane z rozwojem CML

Warto podkreślić, że niektóre czynniki, powszechnie kojarzone z innymi nowotworami, nie wydają się mieć znaczącego wpływu na rozwój CML:¹

Dziedziczność – CML nie jest chorobą dziedziczną. Zmiany genetyczne prowadzące do powstania chromosomu Philadelphia występują spontanicznie w ciągu życia i nie są przekazywane z pokolenia na pokolenie.¹²³
Palenie tytoniu – w przeciwieństwie do wielu innych nowotworów, palenie tytoniu nie jest uznawane za istotny czynnik ryzyka CML.¹
Dieta – nie udowodniono związku między dietą a rozwojem CML.¹
Infekcje – w przeciwieństwie do niektórych innych białaczek, CML nie jest kojarzona z zakażeniami wirusowymi.¹

Inicjujące czynniki mutacji BCR-ABL

Mimo znacznego postępu w zrozumieniu molekularnych mechanizmów CML, dokładna przyczyna inicjująca translokację chromosomową t(9;22) pozostaje nieznana w większości przypadków.¹² Nawet w przypadku pacjentów narażonych na wysokie dawki promieniowania, rozwój CML następuje zwykle po wielu latach od ekspozycji, co sugeruje złożony, wieloetapowy proces patogenezy.¹

Uważa się, że mutacja BCR-ABL występuje losowo w pojedynczej komórce macierzystej szpiku kostnego, nadając jej przewagę proliferacyjną nad zdrowymi komórkami.¹² Ta komórka daje początek klonalnej ekspansji komórek białaczkowych, które z czasem zastępują normalną hematopoezę.¹

Modele doświadczalne CML

Badania na modelach zwierzęcych potwierdziły kluczową rolę genu BCR-ABL w rozwoju CML. Stworzono modele myszy, które rozwijają chorobę podobną do CML po otrzymaniu komórek szpiku kostnego zakażonych wirusem zawierającym gen BCR-ABL.¹ W innych modelach zwierzęcych wykazano, że białka fuzyjne przekształcają normalne komórki prekursorowe krwi w komórki nowotworowe.¹

Podsumowanie etiologii CML

Przewlekła białaczka szpikowa jest unikalnym przykładem nowotworu, w którym pojedyncza zmiana genetyczna (translokacja chromosomowa prowadząca do powstania genu fuzyjnego BCR-ABL) odgrywa kluczową rolę w patogenezie choroby.¹² Chociaż znamy molekularny mechanizm rozwoju CML, pierwotne przyczyny tej translokacji pozostają w większości przypadków niewyjaśnione.¹

Zidentyfikowane czynniki ryzyka obejmują głównie ekspozycję na wysokie dawki promieniowania jonizującego, starszy wiek i płeć męską.¹² W przeciwieństwie do wielu innych nowotworów, CML nie wydaje się być związana z dziedzicznością, paleniem tytoniu, dietą czy infekcjami.¹

Zrozumienie etiologii CML, a w szczególności roli kinazy tyrozynowej BCR-ABL, doprowadziło do opracowania ukierunkowanych terapii (inhibitorów kinazy tyrozynowej), które znacząco zmieniły rokowanie pacjentów z tym schorzeniem.¹²

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Materiały źródłowe

#1 Chronic Myeloid Leukemia (CML) – Hematology and Oncology – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/chronic-myeloid-leukemia-cml
Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature granulocytes. […] The Philadelphia (Ph) chromosome is present in 90 to 95% of cases of chronic myeloid leukemia. The Ph chromosome is the product of a reciprocal translocation between chromosomes 9 and chromosome 22, t(9;22). During this translocation, a piece of chromosome 9 containing the oncogene ABL is translocated to chromosome 22 and fused to the BCR gene. The chimeric fusion gene BCR-ABL is responsible for production of the oncoprotein bcr-abl tyrosine kinase. […] CML ensues when an abnormal pluripotent hematopoietic progenitor cell initiates excessive production of all myeloid lineage cells, primarily in the bone marrow but also in extramedullary sites (eg, spleen, liver). […] Tyrosine kinase inhibitors inhibit the BCR-ABL oncogene, which is responsible for induction of CML. […] Chronic myeloid leukemia (CML) involves a chromosomal translocation that creates the Philadelphia chromosome, t(9;22).
#1 Chronic myelogenous leukemia – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/chronic-myelogenous-leukemia/symptoms-causes/syc-20352417
Most people with chronic myelogenous leukemia have a chromosome called the Philadelphia chromosome inside their blood cells. […] The Philadelphia chromosome forms when chromosome 9 and chromosome 22 break and exchange parts. This creates a short chromosome 22 and a new combination of instructions for the cells. These new instructions can lead to the development of chronic myelogenous leukemia. […] Chronic myelogenous leukemia happens when something causes changes to the bone marrow cells. It’s not clear what starts this process. However, doctors have discovered how it progresses into chronic myelogenous leukemia. […] Genes from chromosome 9 combine with genes from chromosome 22 to create a new gene called BCR-ABL. The BCR-ABL gene tells the blood cells to produce too much of a protein called tyrosine kinase. Tyrosine kinase promotes cancer by allowing certain blood cells to grow out of control.
#1 Chronic Myeloid Leukemia (CML) > Fact Sheets > Yale Medicine
https://www.yalemedicine.org/conditions/chronic-myeloid-leukemia-cml
Some non-inherited genetic abnormalities put people at risk for certain diseases, including chronic myeloid leukemia, a type of blood cancer. […] A genetic abnormality that occurs during a persons lifetime (rather than one that has been inherited from a parent) causes chronic myeloid leukemia. Its not possible to pass this abnormality along to children. […] When chromosome 22 mutates this way, its known as a Philadelphia chromosome. Its presence confirms chronic myeloid leukemia. […] When chromosomes 9 and 22 exchange genetic material, it leads to the creation of a new gene, called BCR-ABL. This gene produces a tyrosine kinase protein that promotes uncontrolled growth of the granulocytes.
#1 Chronic Myeloid Leukaemia (Causes, Symptoms and Treatment)
https://patient.info/doctor/chronic-myeloid-leukaemia-pro
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder of pluripotent haemopoietic stem cells, affecting one or all cell lines (erythroid, platelet and myeloid). Over time, the leukaemic cells proliferate due to stepped-up production and failed apoptosis. More than 90% of cases of CML result from a cytogenetic aberration known as the Philadelphia chromosome. […] The initiating event or events are unknown: there are no known hereditary, familial, geographic, ethnic or economic associations. There may be an increased risk after exposure to the atomic bombs dropped on Hiroshima and Nagasaki but not with lower levels of radiation. […] CML is characterised by a consistent cytogenetic abnormality – a reciprocal translocation between the long arms of chromosomes 22 and 9, t(9;22). The result is a shortened chromosome 22, known as the Ph chromosome. The translocation is significant because it places an oncogene (abl) from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The BCR-ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. This constitutively active BCR-ABL tyrosine kinase causes CML but how the presence of this oncoprotein leads to the CML phenotype is not fully understood. […] CML’s hallmark is the presence of BCR-ABL rearrangement and is considered diagnostic when present in a patient with clinical manifestations of CML.
#1 Overview of the treatment of chronic myeloid leukemia – UpToDate
https://www.uptodate.com/contents/overview-of-the-treatment-of-chronic-myeloid-leukemia
Chronic myeloid leukemia (CML; previously called chronic myelogenous leukemia) is a myeloproliferative neoplasm (MPN), in which cells of the granulocytic lineage are the predominant proliferative component. CML is associated with the Philadelphia chromosome, t(9;22)(q34;q11), which creates a BCR::ABL1 fusion gene (figure 1). This genetic abnormality encodes the constitutively active tyrosine kinase BCR::ABL1, which is essential to the development of CML and is the primary target for treatment of CML. […] CML shares the following biologic features with the other MPNs, namely, polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Stem cell origin â Clonal disorders that arise in a hematopoietic stem or early progenitor cell; Dysregulated proliferation â Dysregulated production of a particular lineage of mature myeloid cells with fairly normal differentiation; Progression to acute leukemia â Variable rates of progression to acute leukemia.
#1 Leukemia, chronic myeloid – Genes and Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK22180/
Chronic myeloid leukemia (CML) is a cancer of blood cells, characterized by replacement of the bone marrow with malignant, leukemic cells. […] CML is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia (Ph) chromosome, named after the city where it was first recorded. The Ph chromosome is the result of a translocation or exchange of genetic material between the long arms of chromosomes 9 and 22. This exchange brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the proto-oncogene ABL (Ableson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth. […] A mouse model has been created that develops a CML-like disease when given bone marrow cells infected with a virus containing the BCR-ABL gene. In other animal models, the fusion proteins have been shown to transform normal blood precursor cells to malignant cells.
#1 Chronic myelogenous leukemia – Wikipedia
https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. […] In most cases, no obvious cause for CML can be isolated. […] Exposure to ionising radiation appears to be a risk factor, based on a 50 fold higher incidence of CML in Hiroshima and Nagasaki nuclear bombing survivors. […] CML was the first cancer to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. […] The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. […] These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.
#1 Chronic myeloid leukemia: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/chronic-myeloid-leukemia/
Chronic myeloid leukemia is caused by a rearrangement (translocation) of genetic material between chromosome 9 and chromosome 22. This translocation, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the fusion gene is often referred to as the Philadelphia chromosome (named for where it was first discovered). The translocation is acquired during a person’s lifetime and is present only in abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited. […] Researchers believe that additional genetic changes play a role in the progression of the chronic phase of chronic myeloid leukemia to the accelerated phase and blast crisis. The most common genetic changes associated with progression to blast crisis include an extra copy of chromosome 8 (trisomy 8), an abnormality of chromosome 17 known as isochromosome 17, and an extra copy (duplication) of the Philadelphia chromosome. When these somatic mutations occur in cells with the Philadelphia chromosome, they likely further promote uncontrolled cell proliferation.
#1 What Is CML? Understanding Chronic Myeloid Leukemia
https://www.iclusig.com/cml/understanding-cml
Chronic myeloid leukemia (CML) starts with an abnormal change, or mutation, in a cells DNA that creates a chromosome known as the Philadelphia (Ph) chromosome. […] When the Ph chromosome is present in cells, a protein known as BCR-ABL is produced. […] The BCR-ABL protein causes the bone marrow to produce abnormal white blood cells. […] These abnormal cells are CML cells. Over time, they overtake healthy white blood cells in the bone marrow to cause leukemia. […] An important goal of treating CML is to reduce the number of leukemia cells in the body. […] TKI treatments may work well to do this. […] However, in some cases after a period of time, CML may stop responding to a particular TKI treatment. This is known as treatment resistance. […] Understand the role mutations may play in treatment resistance.
#1 Chronic Myelogenous Leukemia (CML): Causes, Symptoms, Treatment
https://www.webmd.com/cancer/lymphoma/cml-need-to-know-first
Chronic myelogenous leukemia (CML) is a cancer that affects your blood cells and bone marrow — the soft part inside your bones where blood cells are made. […] The disease starts with a problem in the genes of your blood cells. Sections of two different chromosomes switch places and make a new abnormal one. […] Most people will never know what caused them to get CML. You don’t typically get it from your parents or from infections. Your smoking habits and diet don’t seem to raise your chance of getting it either. […] The only known risk is if you’ve been in contact with high levels of radiation.
#1 Risk Factors for Chronic Myeloid Leukemia | American Cancer Society
https://www.cancer.org/cancer/types/chronic-myeloid-leukemia/causes-risks-prevention/risk-factors.html
A risk factor is something that affects a person’s chance of getting a disease such as cancer. […] The only risk factors for chronic myeloid leukemia (CML) are: […] Radiation exposure: Being exposed to high-dose radiation (such as being a survivor of an atomic bomb blast or nuclear reactor accident) increases the risk of getting CML […] Age: The risk of getting CML goes up with age […] Sex: In general, leukemia is more common in men than women. This includes CML that is slightly more common in males than in females. The reason for this is not clear. […] There are no other proven risk factors for CML. The risk of getting CML does not seem to be affected by smoking, diet, exposure to chemicals, or infections. And CML does not run in families.
#1 Chronic Myeloid Leukemia (CML) – Blood Disorders – Merck Manual Consumer Version
https://www.merckmanuals.com/home/blood-disorders/leukemias/chronic-myeloid-leukemia-cml
Chronic myeloid leukemia (CML) may affect people of any age and of either sex but is uncommon in children younger than 10 years. The disease most commonly develops in adults between the ages of 40 and 60. The cause usually is a rearrangement of two particular chromosomes (9 and 22) into what is called the Philadelphia chromosome. The Philadelphia chromosome produces an abnormal enzyme (tyrosine kinase), which is responsible for the abnormal growth pattern increased production of the white blood cells in CML. […] Additional gene abnormalities (called mutations) that make CML more resistant to treatment sometimes occur.
#1 Risks and causes of chronic myeloid leukaemia (CML) | Cancer Research UK
https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/risks-causes
We dont know what causes most cases of chronic myeloid leukaemia (CML). But we do know that exposure to radiation can increase your risk of developing CML. […] Some studies show radiation can increase your risk of CML. Researchers found that atomic bomb survivors had an increased risk of leukaemia. There is a 20 year study of the workers who cleaned up after the Chernobyl nuclear power plant accident in 1986. It showed that even at low doses of radiation there is an increased risk of all types of leukaemia.
#1 Chronic myelogenous leukemia (CML) Information | Mount Sinai – New York
https://www.mountsinai.org/health-library/diseases-conditions/chronic-myelogenous-leukemia-cml
Chronic myelogenous leukemia (CML) is cancer that starts inside the bone marrow. This is the soft tissue in the center of bones that helps form all blood cells. […] The cause of CML is related to an abnormal chromosome called the Philadelphia chromosome. […] Radiation exposure can increase the risk of developing CML. Radiation exposure can be from radiation treatments used in the past to treat thyroid cancer or Hodgkin lymphoma or from a nuclear disaster. […] It takes many years to develop leukemia from radiation exposure. Most people treated for cancer with radiation do not develop leukemia. And most people with CML have not been exposed to radiation.
#1 Chronic myeloid leukaemia (CML) | Macmillan Cancer Support
https://www.macmillan.org.uk/cancer-information-and-support/leukaemia/chronic-myeloid-leukaemia-cml
CML develops when some white blood cells start behaving abnormally. […] It is not clear why people get CML. It is not linked to smoking, diet, exposure to chemicals or infections. It also does not run in families. Like other cancers, CML is not infectious and cannot be passed on to other people. […] There are some factors that might increase the risk of developing CML. […] CML can develop at any age. But it is more common as people get older. Over half of people diagnosed with CML in the UK are over the age of 60. […] CML is slightly more common in men than women, but the reason for this is not known. […] Exposure to very high radiation levels increases the risk of developing CML. For example, these might be high levels of radiation following a nuclear accident. Very few people in the UK will be exposed to radiation levels high enough to increase their risk of CML. […] Research has found no link between the risk of developing CML and living near nuclear power stations, exposure to electro-magnetic fields, living near high-voltage electricity cables, or household radon (naturally occurring gas).
#1 Chronic Myelogenous Leukemia (CML): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/199425-overview
CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome. […] The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Risk-Factors.aspx
Chronic myeloid leukaemia or CML often begins when there is a change in the structure of DNA that affects the regulation of growth and maturity of the stem cells that produce white blood cells, red blood cells and platelets. […] The cause or trigger that can lead to the mutation of the DNA and make it cancerous is still unknown. […] There is some evidence that long term exposure to the chemical benzene leads to an increased risk of chronic myeloid leukaemia. […] The risk of getting CML rises with age. […] Exposures to pesticides among agriculture workers, exposure to chemicals among rubber or plastic manufacture workers, cleaners, builders labourers, hairdressers etc. have all been studied as risk factors for developing CML.
#1 Chronic Myeloid Leukemia (CML) | Learn What Is CML | LLS
https://www.lls.org/leukemia/chronic-myeloid-leukemia
Chronic myeloid leukemia (CML) is also called chronic myelogenous leukemia, chronic granulocytic leukemia and chronic myelocytic leukemia. CML is one of four main types of leukemia. […] All cases of CML are caused by the BCR::ABL1 fusion gene. This gene is not found in normal blood cells. […] For most people who have chronic myeloid leukemia (CML), there are no obvious reasons why they develop the disease. No one is born with CML. It happens when there is an injury to the DNA of a single bone marrow cell.
#1 What is Chronic Myeloid Leukemia?
https://www.healthline.com/health/chronic-myelogenous-leukemia-cml
Chronic myelogenous leukemia (CML) is also called chronic myeloid leukemia, chronic myelocytic leukemia, and chronic granulocytic leukemia. […] CML is caused by a genetic mutation. Doctors do not know what causes the initial mutation. But they do know the genetic mutation that leads to CML is not passed on by parents. […] In individuals with CML, part of chromosome 9 is switched with a piece of chromosome 22. This makes a short chromosome 22 and a very long chromosome 9. […] According to Mayo Clinic, the short chromosome 22 is called the Philadelphia chromosome, and is present in 90 percent of CML patients. Genes from chromosomes 9 and 22 combine to form the BCR-ABL gene that enables specific blood cells to multiply uncontrollably, causing CML.
#2 Acute myelogenous leukemia – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/acute-myelogenous-leukemia/symptoms-causes/syc-20369109
It’s often not clear what causes acute myelogenous leukemia. […] Healthcare professionals know that it starts when something causes changes to the DNA inside cells in the bone marrow. […] The changes that lead to acute myelogenous leukemia are thought to happen in cells called myeloid cells. […] The DNA changes cause the myeloid cells to make a lot of immature white blood cells, called myeloblasts. […] Many people with AML have no known risk factors, and many people who have risk factors never develop the cancer.
#2 Chronic Myelogenous Leukemia (CML): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/199425-overview
CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome. […] The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.
#2 What Causes Chronic Myeloid Leukemia? | American Cancer Society
https://www.cancer.org/cancer/types/chronic-myeloid-leukemia/causes-risks-prevention/what-causes.html
Normal human cells grow and function based mainly on the information contained in each cell’s chromosomes. […] Over the past few years, scientists have made great progress in understanding how certain changes in DNA can cause normal bone marrow cells to become leukemia cells. In no cancer is this better understood than in chronic myeloid leukemia (CML). […] Most cases of CML start during cell division, when DNA is „swapped” between chromosomes 9 and 22. […] This is known as a translocation and it makes a chromosome 22 that’s shorter than normal. This new abnormal chromosome is called the Philadelphia chromosome. The Philadelphia chromosome is found in the leukemia cells of almost all patients with CML. […] The swapping of DNA between the chromosomes leads to the formation of a new gene (an oncogene) called BCR-ABL. This gene then produces the BCR-ABL protein, which is the type of protein called a tyrosine kinase. This protein causes CML cells to grow and divide out of control. […] Sometimes people inherit DNA mutations from a parent that greatly increase their risk of getting certain types of cancer. But mutations passed on by parents do not cause CML. DNA changes related to CML occur during the person’s lifetime, rather than having been inherited before birth.
#2 Chronic Myeloid Leukemia – Causes
https://www.medindia.net/health/conditions/chronic-myeloid-leukemia-causes.htm
95% of CML patients report the presence of a specific marker, the Philadelphia (Ph) chromosome. […] CML is characterized by the presence of a specific marker, a chromosomal abnormality called the Philadelphia (Ph) chromosome. Approximately 95% of those suffering from CML harbor this abnormality. The Ph chromosome results from a translocation of genes located on the long arms of chromosomes 9 and 22. […] The 9:22 translocation brings two different genes together – the breakpoint cluster region gene (BCR), on chromosome 22 and the Ableson leukemia virus gene (ABL), a proto-oncogene, on chromosome 9. The resulting hybrid gene, the BCR-ABL codes for a protein, endowed with tyrosine kinase activity, which has the ability to activate signal transduction pathways. This protein fosters uncontrolled cell proliferation and genomic instability.
#2 Chronic myeloid leukemia: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/chronic-myeloid-leukemia/
Chronic myeloid leukemia is caused by a rearrangement (translocation) of genetic material between chromosome 9 and chromosome 22. This translocation, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the fusion gene is often referred to as the Philadelphia chromosome (named for where it was first discovered). The translocation is acquired during a person’s lifetime and is present only in abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited. […] Researchers believe that additional genetic changes play a role in the progression of the chronic phase of chronic myeloid leukemia to the accelerated phase and blast crisis. The most common genetic changes associated with progression to blast crisis include an extra copy of chromosome 8 (trisomy 8), an abnormality of chromosome 17 known as isochromosome 17, and an extra copy (duplication) of the Philadelphia chromosome. When these somatic mutations occur in cells with the Philadelphia chromosome, they likely further promote uncontrolled cell proliferation.
#2 About leukemia – CML – Recent diagnosis – Blood Cancer UK Online Community Forum
https://forum.bloodcancer.org.uk/t/about-leukemia-cml/12065
Your white blood count is responding well to the Imatinib and this is very important. Tyrosine kinase inhibitors (TKIs) like Imatinib work by stopping your cells from producing a protein called a tyrosine kinase, which is made by the abnormal BCR::ABL1 gene in the Philadelphia chromosome. This protein causes leukaemia cells to divide more quickly and live longer than healthy blood cells. So by blocking this protein it allows normal cells to be present and work for you. […] It is unlikely that you will become neutropenic as Imatinib does not kill normal cells.
#2 Chronic Myeloid Leukemia (CML) – Blood Disorders – Merck Manual Consumer Version
https://www.merckmanuals.com/home/blood-disorders/leukemias/chronic-myeloid-leukemia-cml
Chronic myeloid leukemia (CML) may affect people of any age and of either sex but is uncommon in children younger than 10 years. The disease most commonly develops in adults between the ages of 40 and 60. The cause usually is a rearrangement of two particular chromosomes (9 and 22) into what is called the Philadelphia chromosome. The Philadelphia chromosome produces an abnormal enzyme (tyrosine kinase), which is responsible for the abnormal growth pattern increased production of the white blood cells in CML. […] Additional gene abnormalities (called mutations) that make CML more resistant to treatment sometimes occur.
#2 What is chronic myeloid leukemia? | Canadian Cancer Society
https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/what-is-chronic-myeloid-leukemia
In chronic myeloid leukemia (CML), the bone marrow makes too many granulocytes. This happens because of a genetic change (mutation) called the BCR-ABL gene. The mutation changes the cells so they don’t become normal granulocytes. […] A specific genetic change to chromosomes causes CML. This is an acquired chromosomal abnormality, which means it occurs sometime after birth. […] The BCR-ABL gene is made when the ABL gene breaks away from chromosome 9 and attaches to the BCR gene on chromosome 22. […] Over time, genetic changes other than the BCR-ABL gene can occur. These mutations stop myeloid blast cells from developing.
#2 Chronic Myeloid Leukemia – Symptoms, Causes and Treatments
https://www.uchealth.com/en/conditions/chronic-myeloid-leukemia
Chronic myeloid leukemia (CML) is a type of leukemia that starts in myeloid cells in the bone marrow. […] There is a change in a chromosome in the cells of almost all patients with CML. The change is called the Philadelphia chromosome. It creates an abnormal gene called BCR-ABL. This causes the leukemia cells to grow out of control. […] Nearly all CML has a genetic change called the Philadelphia chromosome, an abnormal gene called BCR-ABL, or both. People with CML also have too many white blood cells. Tests are used to look for these changes. […] The phase of CML is one of the most important things to know when deciding how to treat this type of leukemia.
#2 Chronic Myeloid Leukemia (CML): Symptoms, Treatment & Prognosis
https://my.clevelandclinic.org/health/diseases/21845-chronic-myelogenous-leukemia-cml
Chronic myeloid leukemia (CML) is blood cancer that starts in the blood-forming myeloid cells or stem cells in your bone marrow. […] People with CML have an acquired genetic mutation or change in myeloid stem cells growing in their bone marrow. Acquired mutations aren’t present at birth and aren’t something you can inherit. Acquired mutations happen during your lifetime. […] In genetic mutations, mutated or changed genes give cells new instructions on what to do. In this case, the mutation creates a new fused gene, BCR-ABL. […] The only risk factor for CML is exposure to high levels of radiation and this applies to very few people. […] Yes, it can. People with CML may have an increased risk of other types of cancer (second cancers). […] No, it can’t. Medical researchers know CML happens when a specific gene mutates, but they haven’t discovered why that mutation happens.
#2 Chronic Myelogenous Leukemia | CML | MedlinePlus
https://medlineplus.gov/chronicmyeloidleukemia.html
The Philadelphia chromosome isn’t passed from parent to child. It happens during your lifetime. The cause is unknown. […] It is hard to predict who will get CML. There are a few factors that could raise your risk: Age – your risk goes up as you get older, CML is slightly more common in men, Exposure to high-dose radiation.
#2 Chronic Myelogenous Leukemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK531459/
Chronic myelogenous leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative neoplasm predominantly composed of proliferating granulocytes and determined to have the Philadelphia chromosome/translocation t(9;22)(q34;q11.2). CML affects both the peripheral blood and the bone marrow. There is an increased incidence of CML among atomic bomb survivors; however, the predisposing risk factors are unknown. […] There is an increased incidence of CML among atomic bomb survivors; however, the predisposing risk factors are unknown.[1]
#2 Risk Factors for Chronic Myeloid Leukemia | American Cancer Society
https://www.cancer.org/cancer/types/chronic-myeloid-leukemia/causes-risks-prevention/risk-factors.html
A risk factor is something that affects a person’s chance of getting a disease such as cancer. […] The only risk factors for chronic myeloid leukemia (CML) are: […] Radiation exposure: Being exposed to high-dose radiation (such as being a survivor of an atomic bomb blast or nuclear reactor accident) increases the risk of getting CML […] Age: The risk of getting CML goes up with age […] Sex: In general, leukemia is more common in men than women. This includes CML that is slightly more common in males than in females. The reason for this is not clear. […] There are no other proven risk factors for CML. The risk of getting CML does not seem to be affected by smoking, diet, exposure to chemicals, or infections. And CML does not run in families.
#2 Chronic myeloid leukaemia (CML) – Leukaemia Foundation
https://www.leukaemia.org.au/blood-cancer/types-of-blood-cancer/leukaemia/chronic-myeloid-leukaemia/
Chronic myeloid leukaemia (CML) is a type of cancer that affects the blood and bone marrow. […] We know that CML is not inherited (passed down from one generation to the next) or contagious. Like other types of leukaemia, CML is thought to arise from an acquired mutation (or change) in one or more of the genes that normally control the growth and development of blood cells. This change or changes will result in abnormal growth. […] Most people diagnosed with CML have a genetic abnormality in their blood cells called the Philadelphia (Ph) chromosome. The Ph-chromosome causes the production of an enzyme called tyrosine kinase which leads to CML. […] Research is going on all the time into possible causes of this damage and certain factors have been identified that may put some people at an increased risk. These include exposure to: radiation â very high doses of radiation, either accidentally (nuclear accident) or therapeutically (to treat other cancers) and chemicals â exposure to industrial chemicals like benzene over a long period of time, or exposure to certain types of chemotherapy to treat other cancers.
#2 Chronic Myelogenous Leukemia (CML): Causes, Symptoms, Treatment
https://www.webmd.com/cancer/lymphoma/cml-need-to-know-first
Chronic myelogenous leukemia (CML) is a cancer that affects your blood cells and bone marrow — the soft part inside your bones where blood cells are made. […] The disease starts with a problem in the genes of your blood cells. Sections of two different chromosomes switch places and make a new abnormal one. […] Most people will never know what caused them to get CML. You don’t typically get it from your parents or from infections. Your smoking habits and diet don’t seem to raise your chance of getting it either. […] The only known risk is if you’ve been in contact with high levels of radiation.
#2 Chronic Myeloid Leukemia (CML) | Learn What Is CML | LLS
https://www.lls.org/leukemia/chronic-myeloid-leukemia
Chronic myeloid leukemia (CML) is also called chronic myelogenous leukemia, chronic granulocytic leukemia and chronic myelocytic leukemia. CML is one of four main types of leukemia. […] All cases of CML are caused by the BCR::ABL1 fusion gene. This gene is not found in normal blood cells. […] For most people who have chronic myeloid leukemia (CML), there are no obvious reasons why they develop the disease. No one is born with CML. It happens when there is an injury to the DNA of a single bone marrow cell.
#2 Chronic myeloid leukaemia (CML) | Macmillan Cancer Support
https://www.macmillan.org.uk/cancer-information-and-support/leukaemia/chronic-myeloid-leukaemia-cml
CML develops when some white blood cells start behaving abnormally. […] It is not clear why people get CML. It is not linked to smoking, diet, exposure to chemicals or infections. It also does not run in families. Like other cancers, CML is not infectious and cannot be passed on to other people. […] There are some factors that might increase the risk of developing CML. […] CML can develop at any age. But it is more common as people get older. Over half of people diagnosed with CML in the UK are over the age of 60. […] CML is slightly more common in men than women, but the reason for this is not known. […] Exposure to very high radiation levels increases the risk of developing CML. For example, these might be high levels of radiation following a nuclear accident. Very few people in the UK will be exposed to radiation levels high enough to increase their risk of CML. […] Research has found no link between the risk of developing CML and living near nuclear power stations, exposure to electro-magnetic fields, living near high-voltage electricity cables, or household radon (naturally occurring gas).
#3 Chronic myelogenous leukemia (CML) Information | Mount Sinai – New York
https://www.mountsinai.org/health-library/diseases-conditions/chronic-myelogenous-leukemia-cml
Chronic myelogenous leukemia (CML) is cancer that starts inside the bone marrow. This is the soft tissue in the center of bones that helps form all blood cells. […] The cause of CML is related to an abnormal chromosome called the Philadelphia chromosome. […] Radiation exposure can increase the risk of developing CML. Radiation exposure can be from radiation treatments used in the past to treat thyroid cancer or Hodgkin lymphoma or from a nuclear disaster. […] It takes many years to develop leukemia from radiation exposure. Most people treated for cancer with radiation do not develop leukemia. And most people with CML have not been exposed to radiation.
#3 Epidemiology and Etiology of Chronic Myeloid Leukemia | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-319-64263-5_2
Although some epidemiological information on Philadelphia (Ph)/BCR-ABL-positive chronic myeloid leukemia (CML) is available, etiological data are still sparse. […] CML can be induced by acute high-dose ionizing radiation exposure or exposure to benzene and some other chemicals. […] Mehlman MA. Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industries. Part XXX: causal relationship between chronic myelogenous leukemia and benzene-containing solvents. Ann N Y Acad Sci. 2006;1076:1109. […] Lamm SH, Engel A, Joshi KP, Byrd DM 3rd, Chen R. Chronic myelogenous leukemia and benzene exposure: a systematic review and meta-analysis of the case-control literature. Chem Biol Interact. 2009;182(2-3):937. […] Bjrk J, Albin M, Welinder H, et al. Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia? Occup Environ Med. 2001;58(11):7227.
#3 Chronic Myeloid Leukaemia (CML) | Fact Sheets
https://www.melbournehaematology.com.au/fact-sheets/chronic-myeloid-leukaemia-cml.html
Chronic myeloid leukaemia (CML) is a malignancy of the white cells of the bone marrow and blood. […] CML occurs when a bone marrow stem cell develops a new but abnormal chromosome called the Philadelphia chromosome (named after the city where it was first discovered). What causes this chromosome to develop in some people is unknown. It does not run in families, and cannot be passed onto children.