Blood cancers, also known as hematologic cancers, are cancers that affect the blood, bone marrow, and lymphatic system. Blood cancers originate when healthy blood cells transform and grow uncontrollably, interfering with the function of normal blood cells. There are several different types of blood cancers, each affecting different blood cell types. The most common blood cancers are leukemia, lymphoma, and myeloma. Understanding how these cancers begin and transform healthy cells into cancerous ones is an important area of cancer research.
What causes blood cancers?
Blood cancers occur when genetic mutations lead to uncontrolled growth and division of blood cells. These mutations cause blood stem cells in the bone marrow to malfunction and overproduce flawed blood cells. Several factors can cause or contribute to the genetic changes that lead to blood cancers:
| Risk Factor | Description |
|---|---|
| Genetic predisposition | Some people are born with genetic mutations or variants that make them more likely to develop blood cancers. For example, Down syndrome is linked to a 10-20 fold increased risk of childhood leukemia. |
| Prior chemotherapy or radiation | Past treatments with chemotherapy or radiation therapy can damage DNA and cause genetic changes that lead to blood cancer later on. |
| Toxins and chemicals | Exposure to certain chemicals like benzene and pesticides is associated with an increased risk of blood cancers. |
| Smoking | Chemicals in tobacco smoke can damage cells and cause genetic changes that lead to cancer. |
| Viruses | Some viruses like Epstein-Barr virus and HTLV-1 virus have been linked to increased blood cancer risk. |
In many cases, it is not one single factor but a combination of genetic, lifestyle and environmental factors that ultimately lead to the development of blood cancer. The gradual accumulation of multiple genetic mutations disrupts normal blood cell growth and enables cancerous cells to thrive.
How do leukemia and lymphoma start?
Leukemia and lymphoma have slightly different origins and paths of transformation.
Leukemia
Leukemia begins in the bone marrow, where blood stem cells divide and mature into different types of blood cells. In leukemia, mutations cause immature white blood cells to proliferate rapidly and fail to develop into normal, infection-fighting cells. These abnormal cells crowd out normal cells in the bone marrow, preventing sufficient production of red blood cells and platelets. Leukemia cells can also spill out into the bloodstream and spread to other organs like the lymph nodes, liver and spleen.
The exact mechanism behind leukemia development is not fully understood, but certain genetic mutations have been identified as drivers of the disease:
– Translocations – Chromosomal rearrangements that fuse two genes together, creating an abnormal mixed gene that promotes cancerous growth. Common in acute myeloid leukemia (AML).
– Epigenetic changes – Altered regulation of gene expression without changes to the DNA sequence. Seen in many leukemia subtypes.
– Signaling proteins – Mutations activating proteins like FLT3 and RAS that transmit growth signals leading to uncontrolled cell division.
– Tumor suppressors – Loss of function in genes like TP53 and ATM that normally prevent cancer growth.
As leukemia progresses, additional mutations accumulate and enable leukemia cells to become more aggressive and resistant to cell death. Diagnosing leukemia early and identifying the specific genetic abnormalities driving it is key for effective, targeted treatment.
Lymphoma
Lymphoma originates in lymphocytes, a type of white blood cell found in the lymphatic system. There are two main categories:
– **Hodgkin lymphoma** – Characterized by the presence of Reed-Sternberg cells, abnormally large malignant lymphocytes. Mutations affecting genes like JAK2 and PDGFRB are thought to drive Hodgkin lymphoma.
– **Non-Hodgkin lymphoma** – A diverse group encompassing any lymphoma without Reed-Sternberg cells. There are over 60 subtypes. Genetic changes affecting BCL2, BCL6, MYC and other genes are frequently involved.
Lymphoma begins when mutations trigger lymphocytes to proliferate abnormally and form tumors in the lymph nodes and other lymphatic tissue. As lymphoma cells multiply uncontrollably, they spread from the lymph nodes to other organs.
Key genetic changes enabling lymphoma development include:
– Chromosomal translocations – Joins two genes together to form a fusion gene, often leading to increased cell growth signals.
– Tumor suppressor loss – Mutations disabling genes that regulate cell growth and survival.
– Oncogene activation – Mutations that enhance the activity of genes that promote cell proliferation.
– Epigenetic alterations – Changes to gene expression through DNA methylation rather than mutation.
Identifying the specific genetic abnormalities fueling each lymphoma case is crucial for targeted therapy.
How does multiple myeloma develop?
Multiple myeloma originates in plasma cells, a type of white blood cell that produces antibodies. In multiple myeloma, mutations occur that cause plasma cells to grow uncontrollably in the bone marrow and form tumor masses called plasmacytomas. Myeloma cells produce abnormal, rather than functional, antibodies. They also release cytokines that break down bone tissue and cause lesions.
The most common genetic abnormalities in multiple myeloma are:
– **Translocations** – Place an oncogene like CYCLIN D under the control of an antibody gene promoter, causing overexpression. t(11;14) is a frequent translocation.
– **Hyperdiploidy** – Gain of multiple chromosomes leads to increased gene expression promoting growth.
– **Mutations** – Commonly affect KRAS, NRAS and TP53 genes. Alter cell proliferation, survival and other functions.
– **Chromosome deletions** – Loss of parts of chromosomes can delete tumor suppressor genes. del(17p) is a high-risk abnormality.
Myeloma develops gradually, with early precursor conditions like monoclonal gammopathy of undetermined significance (MGUS) progressing over many years through various intermediary stages before becoming full multiple myeloma. The accumulation of multiple genetic changes facilitates this transformation process.
How are chronic blood cancers different?
While acute blood cancers like leukemia arise rapidly from a series of mutations, chronic blood cancers like chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS) tend to evolve slowly over many years. They originate when blood stem cells acquire early genetic changes that initially cause subtle dysfunctions in blood cell production.
Some differences between acute and chronic blood cancer development:
| Acute Blood Cancers | Chronic Blood Cancers | |
|---|---|---|
| Speed of onset | Rapid onset over days/weeks | Gradual onset over years |
| Genetic changes | Multiple mutations accumulate quickly | Step-wise accumulation of few mutations |
| Origins | Develop from normal blood cells | Arise from pre-leukemic stem cells |
| Course | Short, aggressive course | Indolent, slowly progressive course |
In chronic blood cancers, affected stem cellsretain some ability to differentiate into mature blood cells, albeit abnormal ones. This leads to the ineffective blood cell production seen in conditions like MDS. Over long periods, further genetic changes accumulate that can transform chronic blood cancers into acute leukemias. Understanding the stepwise process of cancer evolution in each patient is key to timing treatment appropriately.
What causes treatment resistance and relapse?
While blood cancers respond well initially to chemotherapy, radiation or targeted drugs, they often come back as resistant, relapsed disease. This is enabled by new mutations that enable cancer cells to evade treatment.
Common mechanisms of treatment resistance and disease relapse include:
– **Subclonal evolution** – Cancer contains diverse subclones with different mutations. Treatment kills sensitive clones but resistant ones survive and expand.
– **Additional mutations** – New mutations arise that make cancer cells treatment-resistant.
– **Minimal residual disease** – Small numbers of cancer cells remain after treatment and later grow back.
– **Cancer stem cells** – Immature cells that are inherently resistant and give rise to new tumor growth.
– **Microenvironment changes** – Treatment alters the area around tumor cells enabling their re-growth.
– **Epigenetic regulation** – Treatment pressure causes epigenetic changes that increase cancer cell survival.
To prevent relapses, it is critical to monitor minimal residual disease and understand how the cancer mutates over time. New immunotherapies and drugs targeting the microenvironment also aim to overcome treatment resistance.
Conclusion
Blood cancers arise through a multi-step process driven by genetic mutations and gradual evolution. Specific molecular changes lead to the uncontrolled growth, survival and spread of blood cancer cells. Understanding this transformation process for each patient enables more accurate diagnosis, prognosis and personalized treatment strategies. Ongoing research continues to uncover new insights into blood cancer initiation, progression and relapse.