Cryptic NUP98/NSD1 Translocations Are Highly Prevalent in FLT3/ITD-Positive Acute Myeloid Leukemia and Lead to High Rate of Induction Failure. Report From Children's Oncology Group
Bibliographic record
Abstract
Abstract Abstract 529 The nucleoporins (NUP) are a family of proteins, which form the building blocks of the nuclear pore complex. Translocations involving NUP family members NUP214 and NUP98 have been reported in acute myeloid leukemia (AML). DEK/NUP214 (also known as DEK/CAN, t(6;9)) is a known translocation in AML that is highly associated with FLT3/ITD and adverse outcome (see presentation by Moraleda P. et al). By Whole Transcript Sequencing (RNA Seq) we identified 2 cases of NUP98/NSD1 fusions by patients with cytogenetically normal (CN-) AML, both with FLT3/ITD. Recent studies by Hollink I. et al demonstrated high prevalence of FLT3/ITD in patients with NUP98/NSD1 translocations and its association with adverse outcome. Given the significant overlap between DEK/NUP214, NUP98/NSD1 fusions and FLT3/ITD, we studied the prevalence of these fusion transcripts in patients with FLT3/ITD to define the prognostic significance of genomic alteration and their contribution to clinical outcome. Pretreatment samples from patients with FLT3/ITD (N=117) as well as those with CN-AML (N=166) treated on COG-AAML0531 underwent evaluation for NUP98/NSD1 fusion transcripts RT-PCR. Fusion transcripts, as well as the break point junction was verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was correlated with disease characteristics and clinical outcome in patients with FLT3/ITD. In patients with FLT3/ITD (N=117) NUP98-NSD1 was detected in 15 patients (13%). Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. There were no significant differences in the median age (11 vs. 13 years, p=0.19) or blast % (85% vs. 80%, p=0.23) at diagnosis between patients with and without NUP98/NSD1. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1; however, WT1 was significantly more common in FLT3/ITD patients with NUP98/NSD1 than in those without it (43% vs. 13%, p=0.01). Complete remission (CR) rates were compared in FLT3/ITD patients with and without NUP98/NSD1. CR rate in those with and without NUP98/NSD1 was 28% vs. 73% (p=0.002). Moreover, FLT3/ITD patients harboring NUP98/NSD1 were also more likely to have post-induction minimal residual disease (MRD) than those without NUP98/NSD1 (75% vs. 40.6%, p=0.03). In addition to patients with NUP98/NSD1, eight additional patients had NUP214/CAN translocation (i.e., t(6;9)), and cumulatively, translocations involving these two NUP genes accounted for 20% of patients with FLT3/ITD. CR rates in FLT3/ITD-positive patients with and without NUP translocations was determined. Those with NUP98 or NUP214 translocations had a CR rate of 40% compared to 74% in those without NUP translocations (p= 0.001). Further, the presence and prognostic significance of NUP98/NSD1 was then evaluated in CN-AML. The prevalence NUP98/NSD1 in this patient population was 7.8%. Of note, seventy-nine percent of the CN-AML patients with NUP98/NSD1 harbored FLT3/ITD as well. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 79.5%, p=0.03). When analyzing CN-AML patients who harbored both NUP98/NSD1 and FLT3/ITD, only 33% achieved CR, whereas all patients who with NUP98/NSD1 without FLT3/ITD achieved CR. Although the CR rate does not appear to be affected, AML patients with FLT3-ITD have higher relapse rates and therefore inferior outcome. We now show that among patients with FLT3/ITD, those with concurrent NUP fusions have a very low-rate of CR and high post-induction MRD than those without this fusion. The high prevalence of FLT3/ITD among NUP patients is likely not random and it is conceivable that NUP and FLT3/ITD have cooperating functional consequences that lead to a distinct leukemic phenotype and enhanced drug resistance. In conclusion, the presence of NUP in FLT3-ITD patients identifies a distinct subgroup of patients with a very high-rate of induction failure. FLT3-ITD patients should be further categorized according to the presence of NUP to improve risk-stratification of pediatric and young adult AML patients and help clinicians to identify those at very high-risk for induction failure. New therapy strategies are needed for this subgroup of patients with highly resistant disease. Disclosures: Loken: Hematologics, Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 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".