Mechanisms of Resistance to Lenalidomide in Del(5q) Myelodysplastic Syndrome Patients
Bibliographic record
Abstract
Abstract Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem/progenitor cell malignancies characterized by the presence of dysplastic bone marrow (BM) cells leading to inefficient hematopoiesis in one or more myeloid lineages. The most common chromosomal alteration in MDS, accounting for ~20% of cases, is defined by interstitial deletion of the long arm of chromosome 5, and these cases comprise a distinctive subtype in MDS termed del(5q) . Patients suffering from del(5q) MDS present with anemia, variable neutropenia and thrombocytosis. Patients are blood transfusion dependent, which over time can lead to high mortality due to iron overload. The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two thirds of treated patients. At the molecular level, LEN cytotoxic activity relies on its binding to the E3-ligase adaptor cereblon (CRBN) selectively leading to CSNK1a protein degradation. Unfortunately, 50% of patients eventually acquire resistance and relapse 2 to 3 years after treatment. Of note, patients at relapse present an increased risk to progress to acute myeloid leukemia. Mutations in the TP53 gene are correlated with resistance to LEN in del(5q) MDS. However, only approximately 20% of patients that become resistant are TP53 mutated. Therefore, there is a medical need to identify drivers of resistance to LEN in del(5q) patients in order to design patient tailored therapies and prevent relapse episodes. To this end, we have collected CD34+ cells from the BM of six del(5q) MDS patients at the time of diagnosis and upon relapse after treatment with LEN and performed whole genome and transcriptome sequencing on these paired samples. By comparing the genome sequencing data at the two time points, we have identified two patients harboring mutations in the TP53 gene: TP53 R273S arises de novo at the resistant stage and TP53 C106Y is existing at diagnosis and expands at relapse. These results are in accordance with previous reports showing strong association of TP53 mutations and resistance to LEN and therefore validate our approach. In addition, we have identified candidate mutations as drivers of the resistant phenotype, which we hypothesize may substitute or cooperate with TP53 mutations, allowing for the malignant del(5q) stem cell survival during LEN treatment and expansion at relapse. Furthermore, RNA-seq data analysis from the paired samples has identified differentially expressed genes shared among all resistant cases and led us to identify novel putative pathways leading to resistance to LEN in del(5q) hematopoietic stem cell. Of note, we did not find any mutation or significant change in the expression of CRBN or CSNK1A1 genes in our cohort of del(5q) MDS patients at relapse, and therefore they do not have a prognostic value for resistance to LEN. The integration of the data obtained in our study will shed light in to the molecular mechanisms leading to resistance to LEN in del(5q) MDS patients and may pave the way for the design of novel and more effective therapies to treat these patients at relapse. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".