BCR-ABL oncogene and Chronic Myelogenous Leukemia in Human (CML)
Abstract
The BCR-ABL oncogene play pathological basis of the chronic myelogenous leukemia (CML) in human. This is due to the reciprocal translocation between chromosome 22 and chromosome 9. The product of the fusion protein of the philadiphea chromosome has shown to have caused intervention with the other cytoplasmic protein causing intervention in the main cellular events resulting in severe induction of proliferation by constitutively activated the tyrosine kinase activity of ABL gene. The drug therapy targeting the tyrosine kinase activity of the fusion protein have shown remarkable response in patients with CML. Other drug called rapamycin targetting mTOR pathway signalling is also shown to have a significant drug therapy with CML patient.
Introduction
Chronic Myelogenous Leukemia (CML) is a malignant myeloproliferative disorder characterized by excessive production of myeloid cells in the bone marrow and accumulation of these cells in the blood circulation. It was back to 1966 when Novell PC and Hungerford DA discovered the association of abnormal shortened form of chromosome 22 with the patients suffering from CML (R.Chopra et al, 1999). This abnormal chromosomes is known as Philadelphia (Ph) chromosome which by the use of quinacrine fluorescence and Giemsa was shown to represent translocation from chromosome 22 to chromosome 9 (R.Chopra et al,1999). Further studies revealed that the translocation involved the ABL-proto oncogene found in chromosome 9 and the break point cluster gene known as BCR on chromosome 22 which generates BCR-ABL fusion genes. The constitutive activated activity of tyrosine kinase of c-ABL on Ph chromosomes was further defined as the pathological principle underlying the over-production of myeloid cells during the initial stage of chronic leukemia and ‘blast crisis’ in acute leukemia.
Identification of molecular defect in CML
The rearrangement between BCR and ABL proto oncogene on the Ph chromosomes shown variability at the molecular level. Consequently, this will be translated into different types of fusion transcripts and proteins with each expressing its individual leukemia phenotype (Perez M et al 2006). This are described through the illustration shown in Figure A. Location of the breakpoints determined different sized sections from BCR fused with 3’ sequences of ABL gene producing three different chimeric protein (p190, p210, and p230). Different products of chimeric protein are shown to cause different clinical phenotype of cancer disorder (Perez M et al 2006).
“In CML, the breakpoints on chromosome 22 are restricted to a central region of the BCR gene called major breakpoint cluster region (M-BCR)” containing five exons parallel to BCR exons 10 to 14. (Perez M et al 2006) “The break usually occurs within introns located between exons b2 and b3 and b4 with the ABL exon a2, forming the fusion gene b2A2 or b3a2, respectively” (Perez M et al, 2005). This BCR-ABL fusion gene is translated into a novel chimeric 210kDA protein named p210. 90% of CML cases are associated with the presence of this specific identification of molecular defect characterized as Ph chromosome p210 (Perez M et al, 2006).
Characterization of the biological role of the molecular defect in CBL development
In normal situation, the ABL protein usually found between the nucleus and cytoplasm but the failure of retaining this property when fused with BCR gene caused the oncoprotein to be mostly remained within the cytoplasm. This explained the significant interaction of this oncoprotein have with the majority of proteins involved in the oncogenic pathway. The juxtaposition of BCR is constitutively activated tyrosine kinase activity of the ABL which subsequently leads to autophosphorylation, increasing phosphotyrosine residues on BCR-ABL oncogene and consequently the binding site of SH2 domains of other proteins. These abnormal interaction with cytoplasmic molecules have cause severe intervention to the key cellular process including the Ras-mitogen-activated protein kinase (MAPK) that inducing excessive proliferation, the Janus-activated kinase (JAK)-STAT pathway causing impairment of transcriptional activity and the phosphoinositide 3-kinase (PI3K)/AKT pathway which triggers apoptosis.
“The amino terminal BCR-encoded sequences of BCR-ABL contains a tyrosine-phosphorylated site that binds the SH2 domain of the adaptor protein GRB2” (Calioni D et al, 2011). Evident have shown that the phosphorylation of BCRTyr177 play critical event for the BCR-ABL mediated leukemogenesis (Calioni D et al, 2011). Figure B illustrate the molecular pathway activated by BCR-ABL and how BCRTyr177 is important in the pathway of leukemogenesis. From the figure, the interaction of BCR-ABL with the cytoplasmic proteins resulted in multiprotein signaling complexes, BCR-ABL/GRB2. This complex recruits Son of Sevenless (SOS) which synergistically convert the inactive GDP-bound form of Ras to an active GTP-bound form. The resulted complex, GRB2/GAB2/SOS caused constitutive activation of the downstream pathway of RAS, and therefore activating mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) abd MAP kinas proteins. These are together causing abnormal cell proliferation. The complex also suppressing the activity of the forkhead O (FOXO) transcription factor resulting in cell survival. It is also induces p27 proteosomal degradation and mTOR activation increasing proliferation of the cell (Calioni D et al, 2011)
C
Molecular targets downstream of BCR-ABL
One important target in the downstream part of BCR-ABL is the PI3K/AKT/mTOR pathway that are responsible in impairing apoptosis of Ph-positive cells. In this signaling, the mTOR controls the transition phase from G1 to S phase of the cell cycle. Rapamycin have shown evidence to inhibit the mTOR signaling, and several Rapamycin are currently undergoing clinical trials.
Kinase inhibitors
Imanitib has become the first the first drug that was introduced to directly target the BCR-ABL tyrosine kinase activity in CML conditions. It has become the standard line therapy for CML patients during the early chronic phase due to its tolerability and response rate.
References
1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocitic leukemia. Science 1960;32:1497–501.
2. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007;7:441–53.
3. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenousleukemia in mice by 210 bcr-abl gene of the Philadelphia
chromosome. Science 1990;87:6649–53.
4. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of achronic myelogenous leukemia-like syndrome in mice with v-abl and
BCR/ABL. Proc Natl Acad Sci U S A 1990;87:6649–53.
5. Callilo et al, Molecular pathway BCR ABL, 2011 Clinical Research CENTRE