Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells

Self Cite

467

374

Recent advances in acute myeloid leukemia (AML) biology and its genetic landscape should ultimately lead to more subset-specific AML therapies, ideally tailored to each patient's disease. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. If one excludes acute promyelocytic leukemia, current AML management still relies largely on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), at least in younger patients who can tolerate such intensive treatments. Nevertheless, progress has been made, notably in terms of standard drug dose intensification and safer allogeneic HSCT procedures, allowing a larger proportion of patients to achieve durable remission. In addition, improved identification of patients at relatively low risk of relapse should limit their undue exposure to the risks of HSCT in first remission. The role of new effective agents, such as purine analogs or gemtuzumab ozogamicin, is still under investigation, whereas promising new targeted agents are under clinical development. In contrast, minimal advances have been made for patients unable to tolerate intensive treatment, mostly representing older patients. The availability of hypomethylating agents likely represents an encouraging first step for this latter population, and it is hoped will allow for more efficient combinations with novel agents.

Section: Aml With Npm1 Gene Mutationmentioning

confidence: 99%

An update of current treatments for adult acute myeloid leukemia

Dombret

Gardin

2016

Self Cite

467

374

Section: Introductionmentioning

confidence: 99%

“…15 This clinical study probably already indicated the sensitivity of NPM1-mutated AML cells for ATRA because it was recently reported that NPM1-mutated AML is vulnerable to the combination of ATRA and arsenic trioxide. 16,17 Better recognition and selection of ATRA-responsive AML patients might therefore be the key to more successful treatment yielding better clinical outcomes for particular AML subgroups.Herein, we investigated the response of primary AML cases with overexpression of EVI-1 to ATRA. We report that cells from EVI-1-positive AML respond to ATRA by induction of differentiation and decreased clonogenic capacity of AML blasts, whereas patients from other AML subgroups lack an ATRA response.…”

mentioning

confidence: 99%

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid

Verhagen

Smit

Rutten

et al. 2016

Key Points• EVI-1-positive AML cases are sensitive to ATRA.Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in ∼10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome.Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients. (Blood. 2016;127(4):458-463) Introduction Acute myeloid leukemia (AML) is a heterogeneous disease that can be classified based on morphology, immunophenotypic features, and, more importantly, cytogenetic aberrations, molecular abnormalities, gene expression, and methylation signatures.1-3 Aberrant expression of the transcriptional regulator ecotropic viral integration site 1 (EVI-1) occurs in ;10% of human adult AML patients and is associated with particularly aggressive disease and a very poor outcome. Up to 95% of EVI-1-positive patients have an overall survival of ,1 year, 4-6 and novel treatment strategies to improve the survival of AML patients with aberrant expression of EVI-1 are urgently needed. For more than 40 years, most AML patients, including the subgroup with EVI-1 overexpression, have been treated with a combination chemotherapy consisting of cytarabine-arabinoside and an antracycline like daunorubicin. 7,8 Importantly, EVI-1-positive AML cases have an extremely poor initial response to the currently used combination chemotherapy; 39% of EVI-1-positive patients do not achieve complete remission after induction therapy, which is in sharp contrast to the 18% of patients in the other AML subgroups. 5To date, none of other tested alternative regimens have proved to be more effective in AML treatment than the combination of cytarabine and an anthracycline. The exception to this is the treatment of acute promyelocytic (APL) patients with all-trans retinoic acid (ATRA), which increased their survival chances significantly and has turned APL from a poor prognostic leukemia to one that can be cured. 9,10 Because treatment of APL patients with ATRA is very s...

“…Examples of this would include the sensitivity of MLL-rearranged leukemias to BET, hDOT1L, and CDK6 inhibitors [78][79][80][81][82] ; of NPM1c leukemias to ATRA1ATO, 83,84 BET inhibitors, and selective inhibitors of nuclear export 85 ; and of IDH2 mutated leukemias to BCL-2 inhibitors. 86 In these associations, no mutation or transcriptional upregulation of the target is evident from molecular studies, however preclinical sensitivity has been demonstrated, with these associations currently being tested in early phase clinical trials.…”

Section: Therapeutic Targeting Of Individual Aml Mutations and The Prmentioning

confidence: 99%

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Grimwade

Ivey

Huntly

2016

375

300

Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.