**1.1 Discovery of leukemias**

The first case of leukemia was described in 1827 by Alfred Velpeau. Velpeau observed in a 63-year-old patient an enlarged spleen and liver associated with fever, weakness, and the presence of blood pus [5]. Later, Alfred Donné described the autopsy of a patient who had an enlarged spleen and semi-purulent blood under a microscope [6].

However, the first description of leukemia was credited to John Hughes Bennett in 1845. Bennett gave a more complete and scientific description of a 28-year-old patient who had postmortem examination with massive enlargement of the liver, spleen, and lymph nodes, in addition to the presence of purulent blood [7]. In the same year, Rudolf Virchow described the autopsy of a 50-year-old female patient with splenomegaly and pus in her blood vessels [8].

In 1852, Bennett described 37 cases of leucocythemia [9]. Later, in 1856, Virchow noted that cases of splenomegaly leukemia had some granular blood cells with irregular or divided nuclei, while patients with lymphadenopathy already had smooth nucleus cells [10]. Virchow proposed two main varieties of chronic leukemia, splenic and lymphatic, which today are identified as leukemia and lymphoma, respectively [11].

The introduction of blood cell staining techniques in 1878 by Paul Ehrlich revolutionized hematology, allowing a differentiation of different types of leukocytes [12]. With this, Ehrlich distinguished lymphoid and myeloid leukemias [13].

#### **1.2 Discovery of Philadelphia chromosome**

The improvement of cytogenetic techniques allowed the study of chromosomal arrangements in various pathological conditions. Thus, specific human disorders were found to be associated with specific chromosomal abnormalities (e.g., Down syndrome, associated with an extra copy of chromosome 21) [14].

In 1960, Peter Nowell and David Hungerford identified a small chromosome in two CML patients. This chromosome was called the Philadelphia (Ph) chromosome, according to the chromosome standardization committee, which suggested that abnormal chromosomes be designated by the name of the city in which they were discovered [11, 14, 15]. The discovery of this chromosome was a very important step in understanding the pathophysiology of CML.

Chromosome banding techniques revolutionized the cytogenetic approach. Thanks to this advance in 1973, Janet Rowley demonstrated that the Ph chromosome was not a simple deletion but a reciprocal and balanced translocation between the long arms of chromosomes 9 and 22 [16]. Still in the 1970s, Herbert Abelson and Louise Rabstein identified the *ABL* gene, located on chromosome 9, position 9q34 [11]. Protein tyrosine kinase *ABL* is related to the processes of regulation of cell proliferation, survival, cell adhesion, and migration [17].

In 1984, Groffen et al., through the cloning of genomic DNA from CML patients, identified chromosome breaks within a limited region on chromosome 22, which they called the breakpoint cluster region (BCR) [18, 19]. Thus, the highly specific presence of the BCR chromosome breakpoint in patients with Ph-positive CML strongly suggested the involvement of this gene in leukemia.

In the formation of the Ph chromosome, the *ABL1* proto-oncogene (Abelson leukemia 1) is translocated from chromosome 9 to the *BCR* gene on chromosome 22 at position 22q11. This process gives rise to the chimeric *BCR-ABL1* gene, which encodes a constitutively active protein tyrosine kinase, considered central in the mechanism involved in chronic phase-chronic myeloid leukemia (CP-CML) [20–22]. Identification of this anomaly is extremely important for the diagnosis of the disease and for treatment purposes.
