Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer

2021 ◽  
pp. 1-6
Author(s):  
Marisa J.L. Aitken ◽  
Christopher B. Benton ◽  
Ghayas C. Issa ◽  
Koji Sasaki ◽  
Musa Yilmaz ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Drug Development ◽  
Fusion Protein ◽  
Reciprocal Translocation ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Familial Occurrence ◽  
Familial Association ◽  
History Of ◽  
History Of Cancer

CML is defined by the presence of an oncogenic fusion protein caused by a reciprocal translocation between chromosomes 9q and 22q. While our molecular understanding of CML pathogenesis has revolutionized drug development for this disease, we have yet to identify many predisposing factors for CML. Familial occurrence of CML has been rarely reported. Here, we describe 2 cases of CML in a 24-year-old woman and in her 73-year-old maternal great aunt. We describe genetic variants in these patients and report on their environmental exposures that may have contributed to CML pathogenesis. The possible familial association of these 2 cases of CML warrants further investigation into more definitive etiologies of this disease.

scholarly journals DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3587
Author(s):  
Benjamin Lebecque ◽  
Céline Bourgne ◽  
Véronique Vidal ◽  
Marc G. Berger
Keyword(s):  
Dna Methylation ◽  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Single Gene ◽  
Clonal Heterogeneity ◽  
Sequencing Technologies ◽  
Genome Wide ◽  
The Impact

Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.

scholarly journals Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship

Cancer ◽  
2016 ◽  
Vol 123 (4) ◽  
pp. 609-616 ◽  
Author(s):  
Paul B. Koller ◽  
Hagop M. Kantarjian ◽  
Graciela M. Nogueras‐Gonzalez ◽  
Elias Jabbour ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
History Of

scholarly journals CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia

RSC Advances ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 828-844
Author(s):  
Tianzhuo Zhang ◽  
Danna Wei ◽  
Tingting Lu ◽  
Dan Ma ◽  
Kunlin Yu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Synergistic Effects ◽  
Imatinib Resistance ◽  
Long Survival

Imatinib (IM) is utilized for targeting the BCR–ABL fusion protein and as such, chronic myeloid leukemia (CML) is considered to be a curable disorder for which patients can achieve a long survival.

scholarly journals Organic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myeloid Leukemia

2019 ◽  
Vol 18 ◽  
pp. 153303381987990 ◽  
Author(s):  
Mohammed Hussein Kamareddine ◽  
Youssef Ghosn ◽  
Antonios Tawk ◽  
Carlos Elia ◽  
Walid Alam ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Drug Delivery Systems ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Delivery Systems ◽  
Treatment Modalities ◽  
Organic Nanoparticles

Chronic myeloid leukemia is a myeloproliferative neoplasm that occurs more prominently in the older population, with a peak incidence at ages 45 to 85 years and a median age at diagnosis of 65 years. This disease comprises roughly 15% of all leukemias in adults. It is a clonal stem cell disorder of myeloid cells characterized by the presence of t(9;22) chromosomal translocation, also known as the Philadelphia chromosome, or its byproducts BCR-ABL fusion protein/messenger RNA, leading to the expression of a protein with enhanced tyrosine kinase activity. This fusion protein has become the main therapeutic target in chronic myeloid leukemia therapy, with imatinib displaying superior antileukemic effects, placing it at the forefront of current treatment protocols and displaying great efficacy. Alternatively, nanomedicine and employing nanoparticles as drug delivery systems may represent new approaches in future anticancer therapy. This review focuses primarily on the use of organic nanoparticles aimed at chronic myeloid leukemia therapy in both in vitro and in vivo settings, by going through a thorough survey of published literature. After a brief introduction on the pathogenesis of chronic myeloid leukemia, a description of conventional, first- and second-line, treatment modalities of chronic myeloid leukemia is presented. Finally, some of the general applications of nanostrategies in medicine are presented, with a detailed focus on organic nanocarriers and their constituents used in chronic myeloid leukemia treatment from the literature.

scholarly journals PS1170 INFLUX/EFFLUX TRANSPORTERS IN CHRONIC MYELOID LEUKEMIA: THE INFLUENCE OF GENETIC VARIANTS ON SUSCEPTIBILITY AND DRUG RESPONSE

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 532
Author(s):  
R.S. Alves ◽  
A. Gonçalves ◽  
J. Jorge ◽  
G. Marques ◽  
A. Barbosa Ribeiro ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Drug Response ◽  
Efflux Transporters

scholarly journals The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

2019 ◽  
Vol 3 (7) ◽  
pp. 1084-1091 ◽  
Author(s):  
Adrian G. Minson ◽  
Katherine Cummins ◽  
Lucy Fox ◽  
Ben Costello ◽  
David Yeung ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Natural History ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Increased Risk ◽  
History Of ◽  
Dose Modifications

Abstract Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.

Induction of remission in patients with acute myeloid leukemia without prolonged myelosuppression using diphtheria toxin-interleukin 3 fusion protein

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7068-7068 ◽  
Author(s):  
A. E. Frankel ◽  
M. A. Weir ◽  
P. D. Hall ◽  
M. Holguin ◽  
C. Cable ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fusion Protein ◽  
Diphtheria Toxin ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Cell Transplant ◽  
Interleukin 3 ◽  
History Of ◽  
Acute Myeloid

7068 The recombinant diphtheria toxin fusion protein, DT388IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3) showed selective cytotoxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo and was prepared for a phase I clinical study (Urieto, Protein Exp Purif 33, 123, 2004). FDA approval (BB IND#11314) and IRB approvals were obtained. Seventy-five AML patients were screened and thirty-one patients treated. The median age of treated patients was 62 years (range, 25- 81 years). There were sixteen males and fifteen females. Disease was de novo in three, first relapse in ten, second relapse in eight, and refractory in ten patients. Four patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. Cytogenetics were unfavorable in ten, intermediate in nineteen, and not done in two. Seven patients were treated with 4 μg/kg, eight patients were treated with 5.3 μg/kg, thirteen patients treated with 7.1 μg/kg, and three patients treated with 9.4 μg/kg DT388IL3. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, hypoxemia, and hypoalbuminemia. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among thirty evaluable patients, we have observed one CR of 8 months duration, two partial remissions (PRs) lasting one and three months and three minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90% and 93% lasting one to two months. Dose escalation is proceeding. No significant financial relationships to disclose.

Natural History of Southeast Asian Chronic Myeloid Leukemia Patients with Different BCR-ABL Gene Variants

2006 ◽  
Vol 116 (2) ◽  
pp. 114-119 ◽  
Author(s):  
C.U. Auewarakul ◽  
S. Huang ◽  
M. Yimyam ◽  
S. Boonmoh
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Natural History ◽  
Myeloid Leukemia ◽  
Southeast Asian ◽  
Gene Variants ◽  
History Of

scholarly journals Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript [see comments]

Blood ◽  
1990 ◽  
Vol 75 (5) ◽  
pp. 1146-1153 ◽  
Author(s):  
L Selleri ◽  
M von Lindern ◽  
A Hermans ◽  
D Meijer ◽  
G Torelli ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Gene Fusion ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Cloning And Sequencing ◽  
Lymphoid Leukemia ◽  
Minimal Sequence ◽  
Central Sequences

Abstract In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph- positive acute lymphoid leukemias (ALL), the bcr-abl gene fusion is identical to CML, while in 50% an alternative fusion between these two genes occurs, in which the central bcr-sequences are absent. This results in transcription of a 7 kb bcr-abl mRNA, encoding a P190bcr-abl fusion protein. Cloning and sequencing of the chimeric part of bcr-abl cDNAs from two Ph-positive CML patients in chronic phase showed that in one patient, as in the Ph-positive ALL, all central bcr sequences are absent, while in the other patient, part of the bcr central sequences are deleted. Therefore, we speculate that the presence of the 7 kb chimeric ALL type mRNA in one of the patients is not sufficient to drive an acute rather than a chronic leukemic process in this case. The deletions of the central bcr-sequences described here define the minimal sequence requirement of the bcr-abl fusion gene in CML patients so far.

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