Leukemia is a malignant clonal disease of hematopoietic stem/progenitor cells, characterized by enhanced self-renewal, uncontrolled proliferation, differentiation blockade, and impaired apoptosis of leukemic cells, which arrest at different stages of cellular development. In the bone marrow and other hematopoietic tissues, leukemic cells proliferate and accumulate excessively, suppressing normal hematopoiesis and infiltrating other organs and tissues.
Based on the degree of differentiation and maturity of leukemic cells and the natural course of the disease, leukemia is classified into two major categories: acute and chronic. Acute leukemia (AL) involves a differentiation block at an early stage, predominantly affecting blasts and early immature cells, with rapid disease progression and a typical natural course lasting only a few months. Chronic leukemia (CL) involves a differentiation block at a later stage, with a predominance of more mature immature cells and fully mature cells. It progresses slowly, with a natural course of several years. Furthermore, AL is subdivided into acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) based on the predominantly affected cell lineage. Chronic leukemia includes chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and rarer types such as hairy cell leukemia and prolymphocytic leukemia.
Etiology and Pathogenesis
The etiology of leukemia in humans remains not fully understood.
Biological Factors
These include viral infections and immune dysfunction. Adult T-cell leukemia/lymphoma (ATL) has been associated with Human T-lymphotropic Virus Type 1 (HTLV-1). After infecting the body, some viruses may integrate into host cells as endogenous viruses, remaining latent and becoming activated by environmental or chemical factors, thereby inducing leukemia. Alternatively, viruses may act as exogenous agents that spread horizontally and directly cause disease. Individuals with certain immune dysfunctions, such as autoimmune diseases, have an increased risk of leukemia.
Physical Factors
Ionizing radiation, including X-rays and gamma rays, has been implicated. The first leukemia case in a radiation worker was reported in 1911. After the atomic bomb attacks on Hiroshima and Nagasaki, leukemia incidence among survivors was found to be 30 times and 17 times higher, respectively, than in non-exposed populations, with AL and CML being predominantly observed. Studies have shown that extensive and high-dose radiation exposure can lead to bone marrow suppression, reduced immune function, DNA mutations, breaks, and recombinations, ultimately resulting in leukemia.
Chemical Factors
Long-term exposure to benzene and benzene-containing organic solvents is associated with leukemia. Ethyleenimine derivatives, such as ethylenediamine mustard, have strong chromosomal mutagenic and leukemogenic effects. Alkylating agents and topoisomerase II inhibitors used in chemotherapy treatments may also induce leukemia. Chemically induced leukemia predominantly manifests as AML.
Genetic Factors
Familial leukemia accounts for approximately 0.7% of all cases. Among monozygotic twins, the leukemia risk for one twin rises to 1 in 5 if the other is affected, a rate 12 times higher than that observed in dizygotic twins. Individuals with Down Syndrome, who exhibit trisomy of chromosome 21, have a leukemia incidence of 50 per 100,000, which is 20 times greater than in the general population. Other conditions associated with increased leukemia risk include Fanconi anemia, Bloom syndrome (characterized by dwarfism and facial telangiectasia), ataxia-telangiectasia, and congenital immunoglobulin deficiency.
Other Hematological Disorders
Certain hematological disorders can progress to leukemia. Examples include myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Additionally, cases have been reported of leukemia secondary to lymphoma or multiple myeloma, although the specific mechanisms remain unclear.
The development of leukemia likely involves multiple steps, with at least two types of molecular events thought to contribute, as outlined by the "two-hit" hypothesis. The first involves decisive mutations in hematopoietic cells caused by various factors, such as mutations in RAS and MYC, which activate particular signaling pathways. This leads to clonal abnormal hematopoietic cell generation with a proliferative and/or survival advantage, often accompanied by impaired apoptosis. The second involves genetic alterations, such as the formation of fusion genes like PML::RARA, which affect certain transcription factors, resulting in blocked or dysregulated differentiation of hematopoietic cells.
To be continued