Philadelphia chromosome positive chronic myeloid leukemia has a progressive course starting in a benign phase and terminating in a blastic phase. In this study, we show that human homolog double minute 2 (HDM2) inhibition, with MI-219Fa novel compound, and consequently p53 stabilization induce chronic myeloid leukemia (CML) blast crisis cells to undergo apoptosis regardless of the presence of the T315I mutation in the BCR-ABL kinase domain. The response to MI-219 is associated with the downregulation of c-Myc and the induction of p21 WAF1. The p53 target and pro-apoptotic proteins PUMA, Noxa and Bax are induced, whereas full length Bid protein decreases with increased activity of pro-apoptotic cleaved Bid, and decrease of Mcl-1 is observed by increased caspase activity. CD95/FAS (FAS antigen) receptor is also induced by MI-219, indicating that both intrinsic and extrinsic apoptotic responses are transcriptionally induced. In addition, p53 protein accumulates in the mitochondrial fraction of treated cells involved in transcription-independent induction of apoptosis. We conclude that HDM-2 inhibition with MI-219 effectively induces p53-dependent apoptosis in most blast crisis CML cells, with or without BCR-ABL mutation(s).
Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML.
Introduction The Standard of Care for early detection of breast cancer in asymptomatic women is screening mammography, which has limitations such as radiation exposure and lower sensitivity to detect cancer in women with high breast density or invasive carcinomas. TriNetra™-Breast is a blood test for the detection of breast cancer associated circulating tumor cells in blood. Previously, this test has been used in a study for breast cancer detection in India, where it has shown a sensitivity of 92.5%. It has since been granted the United States Food and Drug Administration (USFDA) Breakthrough Device Designation, attesting its potential to provide for improved detection of breast cancer. This prospective, observational, case-cohort study will confirm the clinical performance characteristics of the technology in the US population. Patients and Methods The primary endpoint of this study will be to determine the sensitivity and specificity of the test for breast cancer screening, using mammography and histopathology confirmed diagnosis (when relevant) as the reference methods. Women ≥40 years, with no prior diagnosis of any cancer and undergoing screening mammography for breast cancer will be eligible for participation in this study. 700 women, representing the diverse ethnic US population, will be enrolled. Cohort A will have 500 women with BI-RADS score of 1, 2, or 3. Among these 500 participants, the age categories of 40-49 years, 50-74 years and >74 years will have 100, 300 and 100 women respectively. Cohort B will have 100 women with suspicion of DCIS (without a suspicion of simultaneous invasive carcinoma) and 50 women each with BI-RADS score of 4 or 5. These study population numbers will ensure optimal representation of in-situ carcinoma, malignant and benign cases. Blood samples will be collected from the enrolled women for TriNetra™-Breast, within sixty (60) days of the screening mammogram. If biopsy is indicated, sample collection will be required prior to the procedure. The lab investigators will be blinded to the clinical information of all participants, including mammography and histopathology results, while the participants and clinical investigators will be blinded to the TriNetra™-Breast test results. The results of TriNetra™-Breast will be compared with the results of mammography and/or histopathology for performance estimation of the test. Study participants will be followed for clinical outcomes for maximum duration of 2 years. Citation Format: Ulka Vaishampayan, Darshana Patil, Wahida Rahman, Stephanie Patterson, Emilija Mitrikeska, Joe Dib. Clinical validation of “TriNetra™-Breast” test for breast cancer screening in a prospective, observational, case-cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-18-02.
3433 The development of Ph− clones with new cytogenetic abnormalities has been reported among CML patients with complete cytogenetic remission (CCR) following diverse therapies such as Interferon and Imatinib (Gleevec). The etiologies for these abnormalities have not been characterized and have been attributed to drug effect, or underlying genetic instability in the bone marrow cells preceding or concomitant to the development of CML. Here we report on 31 patients in CCR who, in addition to standard karyotyping, were also analyzed by high-resolution SNP 6.0 array-based genomic copy number analysis. Of the 31 patients studied, 18 were male and 13 female. Their median age was 51 (range 19–71 years). Patients were in CCR for durations ranging from 6+ months to 156+ months (median duration of 24+ months). The duration of major molecular response (MMR) was similar to the duration of the CCR, apart from one patient where it was shorter (36 months versus 84 months). Past medical therapies included Imatinib only in 17 patients, Interferon-α followed by Imatinib in 11 patients, and Interferon only in 3 patients. Two of the patients also received low-dose Cytarabine in addition to Interferon and Imatinib, four received Dasatinib in addition to Interferon and Imatinib, and one received Nilotinib in addition to Imatinib. At the time of the sample collection four of the patients received Dasatinib, one received Nilotinib, three patients received no treatment, and 23 received continuous treatment with Imatinib. Cytogenetic testing disclosed normal karyotype in 24 of the patients. In two of the patients cytogenetic abnormalities were seen in only 1/20 analyzed cells – a finding not considered significant. Of the remaining patients, one had del20q in 11/20 analyzed cells. One had inversion of chromosome 12q (q15, q24.1 in 30/30 cells). One patient had an additional Y chromosome in 2/20 cells, one had deletion of the Y chromosome on 6/20 cells, and one had an extra chromosome 9 in 2/20 analyzed cells. SNP 6.0 array profiling was done on paired DNA samples from purified CML patient-derived CD34+/CD38- cells as well as buccal DNA. Data were analyzed using the previously validated software tool dChipSNP. Acquired genomic copy number aberrations (aCNA) were identified through visual inspection of paired heatmap displays and polymorphic copy number variants (CNVs) excluded. In total, one aCNA was identified in this cohort that was located on chromosome 20 (case #1 with corresponding cytogenetic finding of deletion of 20q) at physical position 30.856–48.002 Mb). Therefore, small or micro-aCNA do not exist in CML patient CCR marrows at appreciable frequencies or at sufficient (>25%) clonal representation. Based on this limited study sample, SNP arrays did not identify any additional genomic changes to the standard karyotype analysis. However, the recurrent presence of low frequency genomically abnormal clones in the bone marrow of these remission patients cannot be ruled out. Disclosures: No relevant conflicts of interest to declare.
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