Leukemia Is Blood Disorder Biology Essay

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Leukemia can be divided into four different types. It is first classified as acute or chronic. In chronic leukemia, the leukemia cells come from mature, abnormal cells. The cells remains as such for too long and accumulate. These types of cells slowly multiply. Acute leukemia develops from early cells, called "blasts," which are young cells that divide frequently. In acute leukemia cells, they don't stop dividing like normal cells do. After being classified as acute or chronic, it is then classified by the type of cells in which the leukemia started. It can either be myelogenous or lymphocytic. Lymphocytic leukemia develops from cells called "lymphoblast" or "lymphocytes" in the blood marrow. The disease can be acute or chronic, referred to as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL). There are several types of lymphocytic leukemia. [1] Myelogenous leukemia develops from myeloid cells. The disease can either be chronic or acute, referred to as chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML). There are several types of myelogenous leukemia. [2]

There are various factors which is responsible for the development of leukemia. Radiation can induce leukemia dose dependently [5,6,7]. Human T-cell leukemia virus is retro virus and has tendency to develop T-cell leukemia [3]. Benzene and its derivative is also potential cause for development of leukemia [14]. Many NSAID's contains benzene in its core so, if taken for longer period of time can show leukemic cell proliferation. As cigarette smoke is also major source of benzene which is inhaled in lungs and transferred to blood which than accumulate into bone marrow leads to some mutations which can develops myeloproliferative disorders. Chromosomal aberrations and translocations are most often found in patient suffering from leukemia. DNA mutations are major cause of leukemia [5]. Overall, the incidence of leukemia is a complex result of the role of multiple factors, genetic predisposition, viruses, radiation, chemical substances may interact, with overlapping roles in the occurrence of leukemia.

Diagnosis is done by Bone marrow aspiration. a bone marrow aspiration and/or biopsy procedure will be carried out to actually look at the fluid and/or tissue ("solid marrow") in the marrow and evaluating the number, size, and shape of each of the cell types, as well as the proportions of mature and immature cells[8,9]. Immunophenotyping or phenotyping by flow cytometry this test can be used to help diagnose leukemia and to determine which type of leukemia a person has [10,11,12].

Leukemia symptoms can occur all of a sudden or gradually. Fever, infection s seen as WBC count gets down. Fatigue, physical exercise intolerance, abdominal pain, or generally feeling fullness, weight loss appears due to reduction in normal erythrocytes. Bleeding is conmen as platelet number is less.

The primary treatment available for leukemia is Chemotherapy, Radiotherapy, Biotherapy, Immunotherapy, Bone marrow transplant and Surgery. radiation is used to kill cancer cells and shrink tumors. Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Surgical removal of the spleen is also a treatment option for chronic leukemia. The spleen collects leukemia cells and they accumulate, allowing the spleen to enlarge. A bone marrow transplant is procedure to replace bone marrow that has been destroyed by treatment with high doses of anticancer drugs or radiation Transplantation may be autologous (an individual's own marrow saved before treatment), allogeneic (marrow donated by someone else), or syngeneic (marrow donated by an identical twin) [13] . Chemotherapy is the use of drugs that either kills cancer cells or preventing the cells from dividing.

ACUTE

CHRONIC

ALL

AML

APL

CLL

CML

Prednisone

Methotrexate

Asparaginase

Doxorubicin

Daunorunicin

Cytarabine

Idarubicine

Mitoxantron

ATRA

Arsenic trioxide

Daunorunicin

Idarubicine

Cyclophosphamide + Vincristine + Prednisone

Fludarabine

Chlorambucil

Rituximab

Alemtuzumab

Imatinib

Dasatinib

Nilotinib

Hydroxyurea

Busulfan

Interferon-α

Table: 1 It shows Medications choice for leukemia [14,15,16,17,18]

ALL- Acute lymphocytic leukemia ;AML- Acute myelogenous leukemia ; APL- Acute promyelocytic leukemia ; CLL-Chronic lymphocytic leukemia ; CML - Chronic myelogenous leukemia ; ATRA-All trans retinoic acid;

Need for Novel target system

As per the table:1 most of the traditional antineoplastic agent used in Leukemia shows many life threatening side effect like mylosuppression, cardiac toxicity, peripheral neuropathy etc. Imatinib mesylate, targets the BCR-ABL kinase as well as a few structurally, related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of Imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. Although the introduction of kinase inhibitors such as Imatinib mesylate has revolutionized the treatment of this disease, several clinical challenges persist. Some patients cannot tolerate the side effects from kinase inhibitors, and in others mutations arise in BCR/ABL rendering it resistant to the effect of kinase inhibitors. In addition, kinase inhibitors do not eradicate the leukemic stem cell, and thus patients need to take these drugs indefinitely. [19]

Figure: 1 It shows resistance developed by blood cells to the Imatinib (BCR-ABL kinase inhibitor) [19]

JAK\STAT inhibitor as novel target for leaukemia

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in the signaling of a wide array of cytokines and growth factors leading to various cellular functions, including proliferation, growth, Hematopoiesis, and immune response.[20,21]

As a stem cell matures it undergoes changes in gene expression with which cell anatomy and physiology changes and makes it closer to specific cell line. This change in gene expression is associated with presence of specific proteins on the cell membrane and its expression. These proteins may be referred as receptor or ligand binding domain and with different receptor and functioning of it makes it closer to its specific cell line.

FIGURE: 2 it shows involvement of cytokines in blood cell development [22,23]

350px-Hematopoietic_growth_factors

Diagram including some of the important cytokines that determine which type of blood cell will be created. SCF= Stem Cell Factor; Tpo= Thrombopoietin; IL= Interleukin GM-CSF= Granulocyte Macrophage-colony stimulating factor; Epo= Erythropoietin M-CSF= Macrophage-colony stimulating factor; G-CSF= Granulocyte-colony stimulating factor ;SDF-1= Stromal cell-derived factor-1; FLT-3 ligand= FMS-like tyrosine kinase 3 ligand ;TNF-a = Tumor necrosis factor-alpha; TGFβ = Transforming growth factor beta.

Red and White blood cells production is regulated in healthy human. When stem cell factor binds to its receptor it triggers proliferation and renewal of cell. After proliferation many glycoprotein growth factor regulates the maturation of the cells which makes it closer to desired cell line or needed cell line. Three more factors that stimulate the production of cells are called colony-stimulating factors (CSFs) and include granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF). These factors act on progenitor cell or the mature cell. Growth factors initiate signal transduction pathways which alters transcription factors and activates genes that determine the differentiation of blood cells. [24]

The binding of cytokines and growth factors to their corresponding receptors activates JAK, which then phosphorylates the receptor and STAT proteins on specific tyrosine residues. STATs then dimerize, translocate to the nucleus, bind to the consensus DNA sequence of 5'-TT(N4-6)AA-3' and initiate the transcription of target genes. [25,26]

FIGURE: 3 It shows structure of the Jak, stat, and socs [35]

Four JAK family kinases, including JAK1, JAK2, JAK3, and TYK2[27,28] and seven STAT family members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6[29] have been identified. JAK 3 found in lymphoid cells and all other are very ubiquitous. The JAKs are structurally has two domain C-terminal kinase domain (JH1) followed by a pseudokinase domain (JH2), which lacks the catalytic activity but has a critical regulatory function. JAKs also have a Src homology 2 (SH2) domain and an N-terminal band four-point-one, ezrin, radixin, moesin (FERM) domain that is critical for mediating the association with cytokine receptors [30,31]. STAT proteins contain a SH2 domain for dimerization and a DNA-binding domain. The amino acid sequence diversity and their tissue-specific distributions account for the diverse roles of STATs in response to extracellular cytokines.

TABLE: 2 It shows role of Jak in Hematopoiesis

Jak

Type

Relevant Phenotypes

Cytokines affected

Reference

Jak 1

Impaired lymphoid development

Defective responses to class 2cytokines and those using gc or gp130 receptor subunits

IL-2, IL-4, IL-6, IL-7, IL-9, IL-10,

IL-15, LIF, all interferons

32

Jak 2

No definitive erythropoiesis

EPO, TPO, IL-3, IL-5, GM-CSF,

IFN-g

33

Jak 3

Defective lymphoid development

Dysregulated myelopoiesis

IL-4, IL-7, IL-9, IL-15

34

The JAK-STAT pathways are up-regulated by cytokines/growth factors. One mechanism for negative regulation of JAK-STAT pathways is through suppresser of cytokine signaling (SOCS) proteins, which directly bind to and inactivate JAKs, and protein inhibitors of activated STATs (PIAS) that bind to phosphorylated STAT dimers, preventing DNA binding. [35, 36]

Abnormal constitutive activation of JAK-STAT pathways has been implicated in various cancers and immune disorders. For example, STAT3 is persistently activated in many tumors, including major carcinomas and some hematologic tumors. Activating mutations in JAK2 have been linked to

Stat Type

Relevant Phenotypes

Cytokines Affected

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