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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The two types of leukemia known as chronic myeloid leukemia and acute lymphoblastic leukemia are associated with the presence of a unique chromosome known as the Philadelphia chromosome which results from a translocation between chromosomes 9 and 22. This results from a fusion of the c-abl gene with the breakpoint cluster (bcr) gene, and, importantly, this new gene is not present in a patient’s healthy cells, thus representing a key opportunity for therapeutic intervention. The resulting Bcr-Abl fusion protein acts as a constitutively active oncogenic tyrosine kinase that causes cell transformation to a malignant phenotype in most CML patients, and in 15–30% of ALL patients. Imatinib (GleevecTM) is now the established frontline treatment for CML and works by binding to the Abl kinase domain of the Bcr-Abl fusion protein, thus inhibiting its tyrosine kinase activity. This results in a normalization of peripheral white blood cell (WBC) counts, and a substantial reduction in the Philadelphia chromosome–positive clones of stem cells in the bone marrow, providing effective hematologic and cytogenetic responses.
Cancer as a genetic disorder
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
A second category of genes involved in cancer is that of the oncogenes, whose activation may predispose to tumour formation. The structure of these oncogenes is homologous to that of particular RNA retroviral sequences. Their normal counterparts, the cellular or proto-oncogenes, present in all individuals, are the site of somatic point mutations or chromosomal rearrangements characteristic of a number of tumour types, especially leukaemias and lymphomas. Thus, the 9/22 translocation characteristic of chronic myeloid leukaemia (the ‘Philadelphia’ chromosome) occurs at the site of the c-ABL oncogene locus on chromosome 9 in most cases of chronic myeloid leukaemia (CML). This results in the generation of a new protein, from the fusion of c-ABL with the BCR gene on chromosome 22, which stimulates unchecked cell division. The elucidation of such mechanisms has opened up important new approaches to the development of rational therapies for particular tumour types, as with the use of tyrosine kinase inhibitors to block the constitutively active BCR-ABL fusion protein in CML.
Interferons and their Mechanisms of Action
Published in Velibor Krsmanović, James F. Whitfield, Malignant Cell Secretion, 2019
The CML chronic phase can be controlled by different therapies including the IFN-α treatment. Recombinant IFN-α2, and IFN-α2 and IFN-α2 have been shown to induce partial or total hematologic remission in up to 90% of the patients with CML in the chronic phase. After several months of IFN therapy, a partial, or sometimes complete, Philadelphia chromosome suppression can be observed in some patients.260-264 In the case of complete cytogenetic conversion, this is accompanied by the loss of an aberrant segment of the bcr gene which is characteristic of the disease.265 This proves, at the DNA level, that a Ph1 chromosome-positive cell population can really be eliminated in some IFN-treated CML patients.
A case of a patient characterized by t(8;22)(p11;q11) and BCR/FGFR1 fusion gene, who was successfully treated with haploidentical hematopoietic stem cell transplantation
Published in Hematology, 2021
Xin Chen, Lifang Huang, Caifeng Zheng, Zhiqiong Wang
The 20 metaphase bone marrow cells showed 46,XY, t(8; 22) (p11; q11), no other abnormal karyotytes were found. (Figure 2(A)) An interphase fluorescence in situ hybridization (FISH) study using the FGFR1 probes revealed division signals in 96% of the cells. The BCR/ABL double fusion probe identified the translocation partner of BCR in metaphase FISH analysis and showed the splitting signal of the BCR probe (three green BCR gene signals and two red ABL gene signals) in 92% of the cells. (Figure 2(B)) The mutation of CSF3R gene (exon 1-17) was detected by second-generation sequencing. Intron mutation was detected at site c.485 + 71A > G (heterozygous sum). According to the current database, the mutation was a single nucleotide polymorphic site and was not pathogenic. Based on these results, the patients were diagnosed with BCR–FGFR1 gene rearrangement of 8p11 myeloproliferative syndrome.
Current strategies for detecting functional convergence across B-cell receptor repertoires
Published in mAbs, 2021
Matthew I. J. Raybould, Anthony R. Rees, Charlotte M. Deane
In addition to prior infection/vaccination history, broader cohort characteristics can also be considered and either held constant, balanced, or varied, depending on the research question. Studies have found the immune response is dependent both on age40–42 and sex,43 and that the properties of response BCRs/antibodies depend strongly on maturation state36 (see below). Another important, yet often under-considered trait, is the geographical origin and/or ancestry of each volunteer. This is relevant since gene loci are under the influence of local environmental pressures, affecting allelic selection which in turn can play a role in disease susceptibility through different induced antibody responses.44–46 For example, IGKV2D-29*02 and IGHV3-23*03 have been found to be significantly overrepresented in North American and Asian populations respectively, correlating with differential ability to engage Haemophilus influenzae type b (Hib),46 while polymorphisms in IGHV1-69 and several IGHV2 loci have been associated with autoimmunity.47,48 A recent study has found that BCR gene recombination profiles can vary even amongst human monozygotic twins,49 so it remains unclear to what extent individual V(D)J recombination preferences can be accounted for by controlling for volunteer genetics. The role of an individual’s microbiome in shaping the nature of the baseline immune repertoire is also becoming apparent.50
Myofibrillogenesis regulator 1 (MR-1): a potential therapeutic target for cancer and PNKD
Published in Journal of Drug Targeting, 2018
Junxia Wang, Wuli Zhao, Hong Liu, Hongwei He, Rongguang Shao
CML is a myeloproliferative neoplasm that is primarily characterised by the constitutive expression of the oncogenic tyrosine kinase breakpoint cluster region (BCR)-Abelson (ABL) encoded by the BCR-ABL fusion gene, the result of a well-known chromosomal translocation that creates the Philadelphia (Ph) chromosome, in which the BCR gene on chromosome 22 is fused to a large part of the Abl-1 gene on chromosome 9 [31]. This fusion protein is a tyrosine kinase that activates multiple proliferative signalling pathways, such as the RAS, c-ABL, PI3K, cyclin D, c-MYC and JAK/STAT pathways [32], resulting in a clonal myeloproliferative disorder of haematopoietic stem cells. CML progression is divided into three stages: chronic phase (CP), accelerated phase and blast phase (BP) [33]. Patients in the CP are often asymptomatic, while the main obvious functional changes in the BP are the severe block in differentiation and apoptosis and the accelerated proliferation [34]. The disease is indolent in the CP, and the leukemic cells retain the ability to differentiate into mature granulocytes; however, in the BP, there are numerous aggressive and immature blast cells. The mechanism underlying the CP to BC transition is still unknown.