**2. Milestone histories and remarkable genetic discoveries of CML**

The remarkable genetic discoveries have been translating into clinical diagnosis, effective, and specific therapies from the following so many FIRST findings.

### **2.1 The first named as a leukemia**

CML was first named as leukemia in the nineteenth century, when it was described and recognized in 1845 from descriptions of the clinical presentations and symptoms by Bennett, Virchow, and Craigie [5–7].

Cells from blood or bone marrow morphology from patient with CML show at every stage differential cells due to partial blockage, unlike the maturation and differentiation of acute leukemia, which are blocked completely in the early cell differential stage. The chronic term of CML refers to maturation and differentiation, unlike other diseases by period of disease duration.

#### **2.2 The first of a live case of CML patient diagnosed**

The first live patient with CML was diagnosed in 1846 by Dr. Henry Fuller, a physician at St George's Hospital in London with the identification of a large proportion of abnormal, granular colorless globules under microscope [8].

#### **2.3 The first used of arsenic in CML treatment**

Fowler's solution, the compounded a potassium bicarbonate-based solution of arsenic trioxide (As2O3) invented by Thomas Fowler named as Fowler's solution in 1786, was first tried in CML among all leukemias in 1865 to reduce the over proliferative white cell numbers [9].

Very excitingly, the arsenic has been used to cure acute promyelocytic leukemia (APL) which it made the worst and incurable type of leukemia; APL became the best therapeutical curable type among all types of leukemias achieved by several Chinese medical researchers [10].

#### **2.4 The first defined as a myeloproliferative disorder**

CML was first introduced as a myeloproliferative disorder based on the evidence accumulated of multiple abnormalities involved in erythroblasts, granulocytes, megakaryocytes, but no fibroblasts in bone marrow by Dameshe [11].

*Milestone Histories and Paradigmatic Genetic Discoveries of Chronic Myeloid Leukemia (CML) DOI: http://dx.doi.org/10.5772/intechopen.90938*

#### **2.5 The first finding of Ph chromosome in leukemia**

Ph chromosome was first reported in 1960 by Nowell and Hungerford [12]. Originally such a finding was described as deletion of the long arm of chromosome 22, although it was thought to be chromosome 21 [13] and was even thought to be the chromosome Y due to limitation of low chromosomal resolution from the cytogenetic technique at that time [14, 15]. The smart conclusion made from this was the suggestion that such chromosome change could be associated with CML.

Since then the detection of Ph chromosome by the application of the cytogenetic (Karyotyping) and the molecular cytogenetic techniques, fluorescence in-situ hybridization (FISH) has become a very useful and practical approach in the diagnosis and monitor of CML. Cytogenetic karyotype analysis is a specific, accurate, low cost, fast technology in CML diagnosis, and disease monitoring in the detection of both classical and variant Ph translocation.

#### **2.6 The first identified as a translocation of chromosomes 9 and 22 in leukemia**

In 1973, Ph chromosome or Ph translocation was identified as balanced translocated chromosomes 9 and 22, t[q34;q11], by Rowley [16]. Such milestone finding identified and classified the Ph chromosome was not the shortening of chromosome 22 as found by Nowell and Hungerford, which it pointed out the direction and narrowed down to the discovery of CML causing gene from the initial finding of the association between Ph chromosome and CML.

#### **2.7 The first finding of BCR-ABL gene in leukemia**

Breakpoint cluster region-Abelson leukemia (BCR-ABL) virus was the first finding from CML in leukemia and oncology. BCR-ABL is a fusion oncogene, resulting in CML from the translocation at the breakpoints of the long arm of chromosome 9 and the long arm of chromosome 22 and in humans [17] and mice [18–20].

Studies found that BCR-ABL fusion gene has several types of isoform protein products from the different breakpoints of translocated. The common types are the fusion protein products (p210, p190, and p230), resulting in the enhancement of tyrosine kinase activity in CML and other types of hematological malignancies in the similar mechanism [21]. The concept from such findings obtained provided the valuable theory for the development of the target-specific therapy afterward.

The detection of BCR-ABL gene using PCR technique commonly has become a valuable/effective and sensitive approach in the diagnosis and disease monitoring of CML, which it does not require cell culture.

#### **2.8 The first clinical therapy by using tyrosine kinase inhibitor (TKI) in leukemia**

CML has a long developmental history in the trial of treatment in the past, including the first trial by using arsenic (Fowler's solution), x-irradiation, nitrogen mustard, busulfan, hydroxyurea, interferon-α, and stem cell transplantation. The tyrosine kinase inhibitor (TKI) is considered as the first and a successfully designed first-generation target therapy in cancer therapies clinically. This therapy was designed on the base of blocking and deregulating the activity of BCR-ABL fusing gene 1998 [22]. The second-generation TKI started to be used for reducing the resistance was developed in 2004. Such specific therapy significantly prolonged lifespan for patients with CML.
