What is leukemia?
Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. Leukemia incidence varies considerably by geography and subtype, according to an analysis of World Health Organization cancer databases. Acute leukemia is a deadly sentence, if not timely diagnosed and treated. With the advent of chemotherapy, about 98% of children with acute lymphocytic leukemia go into remission within weeks after starting treatment and 90% are in remission after 10 years. However, in lower middle-income countries, survival can be as poor as 20-50% at 10 years, for the untimely referral to care, unavailability of specialized diagnostics and cytotoxic treatments along with supportive care. The access to cure is unavoidably linked to the appropriate diagnosis, where different subtypes of leukemia require specific protocols of cure: indeed, it is essential to be able to clarify the prognosis and aggressive (acute) or more indolent (chronic) course of the disease, if arising from myeloid or lymphoid lineages of blood cells, assisting different patterns of spread and relapse, and when special subtypes are suggested - for which highly effective tailored treatments may exist.
Types of leukemia
The main types of leukemia are acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and other types. ALL is the most common type of leukemia in young children. ALL can also occur in adults. AML is a common type of leukemia. It occurs in children and adults. AML is the most common type of acute leukemia in adults. CLL is the most common chronic adult leukemia, you may feel well for years without needing treatment. According to WHO, CLL is the most common form of leukemia in the Western world, but is significantly less frequent in Asia. CML mainly affects adults. A person with CML may have few or no symptoms for months or years before entering a phase in which the leukemia cells grow more quickly. There are also rarer types of leukemia, including hairy cell leukemia, myelodysplastic syndromes and myeloproliferative disorders.
Risk factors for leukemia
People who've had certain types of chemotherapy and radiation therapy for other cancers have an increased risk of developing certain types of leukemia. Genetic abnormalities seem to play a role in the development of leukemia. Certain genetic disorders, such as Down syndrome, are associated with an increased risk of leukemia. Exposure to certain chemicals, such as benzene, which is found in gasoline and is used by the chemical industry, is linked to an increased risk of some kinds of leukemia. Smoking cigarettes increases the risk of acute myelogenous leukemia. If members of your family have been diagnosed with leukemia, your risk of the disease may be increased.
Cancer biomarkers are molecular indicators of a biological status, often produced by the tumor itself or the host system in response to the tumor, and can be used for early detection, diagnosis, prognosis, and prediction of response to treatment and cancer recurrence. The following are several common biomarkers in leukemia.
Ikaros is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia.
Casein Kinase II (CK2) is a pro-oncogenic kinase that is overexpressed in several cancers, including leukemia. CK2 is a ubiquitous, serine/threonine kinase that is involved in multiple signaling pathways and has over 300 substrates. CK2 phosphorylates Ikaros at multiple evolutionarily-conserved serine/threonine amino acids, which impairs Ikaros' ability to bind DNA and localize to peri-centromeric heterochromatin. A fine balance of CK2- and protein phosphatase 1 (PP1)-mediated post-translational modification of Ikaros determines Ikaros' stability and activity. In leukemia, as well as other malignancies, the expression and activity of CK2 is increased, which results in functional inactivation of Ikaros and loss of its tumor .suppressor function.
Figure 1.Mechanism of action of CK2 inhibitor via Ikaros.( Chandrika G, et al. 2019)
Structural maintenance of chromosomes protein 3 (SMC-3) is a nuclear protein that in humans is encoded by the SMC3 gene. A post-translated modified form that is excreted is known as basement membrane-associated chondroitin proteoglycan. SMC stands for Structural Maintenance of Chromosomes. SMC proteins represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics.
FOX proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.
β-catenin is a protein that in humans is encoded by the CTNNB1 gene. β-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcription.
Voltage-dependent anion-selective channel protein 1 (VDAC1) encodes for a protein product length of 283. VDAC1 regulates the flux of mostly anionic metabolites through the outer mitochondrial membrane, which is highly permeable to small molecules. VDAC is the most abundant protein in the outer membrane. Changes in membrane potentials can switch VDAC between open or high-conducting and closed or low-conducting forms.
Table 1. Protein-based biomarkers for the detection of leukemia cancer
|Types of leukemia cancer||Biomarkers|
|ALL||voltage-dependent anion-channel protein1(VDAC1)，CK2，Ikaros|
|AML||FOX, SMC-3, MAPKBP1, Siglec-5|
|CML||Akirin-2, NFκB-p65, β-catenin|
|CLL||VDAC1, MAVS, AIF and SMAC/Diablo|
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2. Gowda C, Song C, Ding Y, et al. Cellular signaling and epigenetic regulation of gene expression in leukemia[J]. Advances in Biological Regulation, 2019: 100665.
3. Gurnari C, Falconi G, De Bellis E, et al. The Role of Forkhead Box Proteins in Acute Myeloid Leukemia[J]. Cancers, 2019, 11(6): 865.