The Molecular Biology of Chronic Myeloid Leukemia

Chronic Myeloid Leukemia is a kind of cancer that affects white blood cells and progresses slowly over a long period. It can strike anyone at any age, but it is most frequent in older persons between the ages of 60 and 65.

Chronic myeloid leukaemia is a clonal myeloproliferative proliferation of primitive hematopoietic progenitor cells that have been altered. It involves Myeloid, monocytic, erythroid, megakaryocytic, B-lymphoid, and T-lymphoid lineages are all involved.

CML was the first human disease in which a specific karyotype aberration — the Philadelphia (Ph) chromosome — was connected to leukemogenesis pathogenetic processes.  It was one of the first neoplasms for which a biologic treatment (interferon) was identified to inhibit the leukemic clone and extend survival. CML affects 1 to 2 people per 100,000 people each year and accounts for 15% of all adult leukaemias.

Philadelphia Chromosome

The Ph chromosome is a shorter version of chromosome 22 caused by a reciprocal translocation between the long arms of chromosomes 9 and 22. It is the hallmark of CML and is found in up to 95 per cent of patients. It is a defining feature of CML and can be observed in up to 95% of patients.

In further scientific investigations, it was found that ABL proto-oncogene normally located on chromosome 9 and BCR gene on chromosome 22 are involved in translocation.

The ABL gene produces a nonreceptor tyrosine kinase. Human ABL is a 145-kD protein that has two isoforms resulting from alternative splicing of the first exon. A 3′ fragment of the ABL gene from chromosome 9q34 is added to the 5′ section of the BCR gene on chromosome 22q11, resulting in a Ph translocation. A chimeric BCR–ABL messenger RNA is produced from a hybrid BCR–ABL gene (mRNA). In the ABL gene, the breakpoint is frequently located 5′ (toward the centromere) of exon 2. Exons 2 to 11 (also known as a2 to a11) of the ABL gene are transposed into the 5.8-kb major breakpoint cluster region (M-bcr) of the BCR gene on chromosome 22 between exons 12 and 16 (also known as b1 to b5). The breakpoints in BCR are either 5′ between exons b2 and b3 or 5′ between exons b2 and b3.

BCR-ABL Signalling Pathway

ABL proteins are nonreceptor tyrosine kinases that play critical functions in signalling and cell growth regulation. The catalytic domain, two SRC homology domains (SH2 and SH3) that regulate ABL’s tyrosine kinase action, and a myristoylation sequence connects ABL to plasma membrane proteins make up the N-terminal section of ABL.

The leukemogenic transformation of BCR–ABL is aided by structural changes in ABL and BCR. BCR’s N-terminal coiled-coil motif boosts its tyrosine kinase activity and allows ABL to bind F-actin. BCR’s serine-threonine kinase domain promotes ABL tyrosine kinase and p210BCR–ABL signalling pathways.

When BCR is fused to ABL at the N-terminus, a significant amino acid sequence is added to ABL’s SH2 region. BCR enables ABL to become constitutively active as a tyrosine phosphokinase by interfering with the neighbouring SH3 kinase regulatory region. The tyrosine phosphokinase activity of p210BCR–ABL and p190BCR–ABL is higher than that of p145ABL, the normal ABL protein.

Various protein-protein interactions are possible due to the structure of p210BCR–ABL, which supports the participation of multiple intracellular signalling pathways. Adapter proteins such as growth factor receptor-bound protein 2 (GRB2) and CRK-oncogene–like protein are bound by many BCR domains.

Chronic Myeloid Leukemia

Chronic myeloid leukaemia is a type of myeloproliferative disorder. Myeloid progenitor cells mature at different rates, are discharged prematurely into the peripheral bloodstream, and settle in extramedullary regions. Changes in myeloid progenitor cells’ proliferative capacity, as well as a shift in the balance between self-renewal and differentiation toward differentiation, appear to be the causes of their chaotic proliferation.

Stem cells enter the proliferating compartment, causing the neoplastic cell population to exponentially expand in subsequent maturational compartments, where they may also be less susceptible to growth-regulatory signals from cytokines or the bone marrow milieu.

Immature hematopoietic Chronic myeloid leukaemia progenitors’ poor adhesion to marrow stromal components may enable their escape into the bloodstream. Hematopoietic progenitor cells cling to extracellular matrix or immobilised growth-regulating cytokines in the normal state.

The inhibition of apoptosis (programmed cell death) pathways has been linked to the development of chronic myeloid leukaemia. Hematopoietic progenitor cells that express p210BCR–ABL are resistant to cytotoxic medicines and irradiation and can survive without relying on growth hormones.

Refractoriness to treatment, leukocytosis with increased blood and marrow blasts, basophilia, unrelated increases or decreases in platelet counts, and clinical manifestations such as unexplained fever, splenomegaly, extramedullary disease, weight loss, and bone and joint pains are all signs of disease transformation.

Cytogenetic alterations may also correspond to molecular problems.

In 90% of CML patients, cytogenetic examination identifies the Ph chromosome. The standard diagnostic test for CML is cytogenetic investigations, which are particularly useful in demonstrating additional karyotypic abnormalities. Molecular study reveals BCR–ABL fusion products in half of the 10% of CML patients whose Ph chromosome cannot be detected by cytogenetic tests.


The study of the molecular processes of Chronic myeloid leukaemia leukemogenesis has progressed significantly. The development of targeted and effective treatments has resulted from the translation of our understanding of molecular processes into the understanding of cellular and phenotypic disease presentations.

After three to five years, an illness that was formerly lethal can now be treated. This progress has been made possible by improvements in transplantation techniques and supportive care, as well as the development of effective anti-CML medications, such as interferon alfa and cytarabine. Tyrosine kinases have been discovered as molecular targets, and molecular therapies (targeted therapy, immunomodulatory therapy, and marrow cleansing) are being used.