Chronic Myeloid Leukemia

Chronic myeloid (myelogenous) leukemia (CML) is a disorder of hematopoietic stem cell, blood cells that give rise to all the other blood cells and are derived from mesoderm (one of the three primary germ layers in the very early embryo). They are located in the red bone marrow, which is contained in the core of most bones. The disorder leads to myeloproliferation, in which the bone marrow makes too many immature white blood cells. In the United States, it is estimated that over 5000 cases of CML are diagnosed yearly with increasing incidence with age and a slight male predominance. Thirty percent of patients are 60 years old or older, with the median age being 45-50 years old. Left untreated the disease progresses to blastic phase in which 20% or more of the cells in the blood or bone marrow are blast cells (immature blood cells). When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis. At this time, clinical picture is indistinguishable from acute leukemia. In most patients, the transition between chronic phase and blastic phase is gradual and manifested by an accelerated phase (AP) characterized by the development of a progressive increase in blast counts, low red blood cell count and development of new chromosomal abnormalities.4


A blast crisis in the case of chronic myelogenous leukemia
Credit: CDC/ Stacy Howard

The instigating factor of chronic myeloid leukemia is the reciprocal translocation between chromosomes 9 and 22, which is associated with the creation of the BCR-ABL fusion oncogene, a hybrid gene formed from two previously separate genes. The gene product of the BCR-ABL gene activates several processes which cause uncontrolled proliferation and survival of CML cells. Chronic myeloid leukemia is a progressive and often fatal myeloproliferative cancer. The acquired chromosomal translocation known as the Philadelphia chromosome (Ph) results in the synthesis of BCR-ABL fusion oncoprotein which is responsible for a wide range of human leukemias. This activates tyrosine kinase, an enzyme that can transfer a phosphate group from ATP to a protein in a cell. Increased blood cobalamin concentrations (hypercobalaminemia) are encountered in chronic myeloid leukemia.



The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). Alternative second-line options include the newer tyrosine kinase inhibitors (TKIs) like dasatinib and nilotinib.2,3 However, despite extraordinary progress, a true cure for CML is not generally achieved by Abl kinase inhibitors. There are several new TKIs in pre-clinical and clinical trials for treatment of patients with CML: Bosutinib, Aurora kinase inhibitors, and Homoharringtonine (cephalotaxine, HHT), a natural alkaloid extract from the seeds of the evergreen tree Cephalotaxus harringtonia. Currently, HHT is being re-evaluated in the treatment of patients with CML who are resistant to imatinib and other TKIs.4 Tetrandrine bisbenzylisoquinoline alkaloid belongs to a series of almost 400 phenylalanine-derived plant metabolites with a rich and varied chemistry and pharmacology. It has been shown to be active against a variety of tumors, such as colon cancer, glioma, ovarian cancer, and hepatocellular carcinoma. Recent studies (2015) have shown that tetrandrine salt that has potent anti-tumor activity against both CML and imatinib-resistant CML cells.5

References

  1. Chronic Myeloid Leukemia – Mechanisms of Resistance and Treatment
  2. Long-Term Outcomes in the Second-Line Treatment of Chronic Myeloid Leukemia
  3. Outcome of Treatment of CML with 2nd Generation Tyrosine Kinase Inhibitors After Imatinib Failure
  4. Advances in treatment of chronic myelogenous leukemia – new treatment options with tyrosine kinase inhibitors
  5. Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis*




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