Gene Summary

Gene:PALB2; partner and localizer of BRCA2
Aliases: FANCN, PNCA3
Summary:This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:partner and localizer of BRCA2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Fanconi Anemia - Complementation Group N

Latest Publications

Khanal S, Galloway DA
High-risk human papillomavirus oncogenes disrupt the Fanconi anemia DNA repair pathway by impairing localization and de-ubiquitination of FancD2.
PLoS Pathog. 2019; 15(2):e1007442 [PubMed] Free Access to Full Article Related Publications
Persistent expression of high-risk HPV oncogenes is necessary for the development of anogenital and oropharyngeal cancers. Here, we show that E6/E7 expressing cells are hypersensitive to DNA crosslinking agent cisplatin and have defects in repairing DNA interstrand crosslinks (ICL). Importantly, we elucidate how E6/E7 attenuate the Fanconi anemia (FA) DNA crosslink repair pathway. Though E6/E7 activated the pathway by increasing FancD2 monoubiquitination and foci formation, they inhibited the completion of the repair by multiple mechanisms. E6/E7 impaired FancD2 colocalization with double-strand breaks (DSB), which subsequently hindered the recruitment of the downstream protein Rad51 to DSB in E6 cells. Further, E6 expression caused delayed FancD2 de-ubiquitination, an important process for effective ICL repair. Delayed FancD2 de-ubiquitination was associated with the increased chromatin retention of FancD2 hindering USP1 de-ubiquitinating activity, and persistently activated ATR/CHK-1/pS565 FancI signaling. E6 mediated p53 degradation did not hamper the cell cycle specific process of FancD2 modifications but abrogated repair by disrupting FancD2 de-ubiquitination. Further, E6 reduced the expression and foci formation of Palb2, which is a repair protein downstream of FancD2. These findings uncover unique mechanisms by which HPV oncogenes contribute to genomic instability and the response to cisplatin therapies.

Duran-Lozano L, Montalban G, Bonache S, et al.
Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T.
Breast Cancer Res Treat. 2019; 174(2):543-550 [PubMed] Related Publications
PURPOSE: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.3201+5G>T identified in a breast cancer family.
METHODS: Peripheral blood RNA was analyzed in two carriers and ten controls by RT-PCR and Sanger sequencing. The splicing profile was also characterized by semi-quantitative capillary electrophoresis and quantitative PCR. RAD51 foci formation and PALB2 LOH status were evaluated in primary breast tumor samples from the carriers.
RESULTS: PALB2 c.3201+5G>T disrupts intron 11 donor splice site and modifies the abundance of several alternative transcripts (∆11, ∆12, and ∆11,12), also present in control samples. All transcripts are predicted to encode for non-functional proteins. Semi-quantitative and quantitative analysis of PALB2 full-length transcript indicated haploinsufficiency in carriers. One tumor exhibited PALB2 LOH and RAD51 assay indicated homologous recombination deficiency in both tumors.
CONCLUSIONS: Our results support a pathogenic classification for PALB2 c.3201+5G>T, highlighting the impact of variants causing an imbalanced expression of natural RNA isoforms in cancer susceptibility.

Ramanagoudr-Bhojappa R, Carrington B, Ramaswami M, et al.
Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.
PLoS Genet. 2018; 14(12):e1007821 [PubMed] Free Access to Full Article Related Publications
Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.

Velázquez C, Esteban-Cardeñosa EM, Lastra E, et al.
A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer.
Breast. 2019; 43:91-96 [PubMed] Related Publications
Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection.

Lott PC, Carvajal-Carmona LG
Resolving gastric cancer aetiology: an update in genetic predisposition.
Lancet Gastroenterol Hepatol. 2018; 3(12):874-883 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Every year gastric cancer accounts for nearly 1 million new cases and more than 720 000 deaths worldwide. Prognosis is dismal because most patients are diagnosed with advanced disease; as such, gastric cancer outcomes will benefit from better methods for identification of at-risk individuals that can be targeted for early detection. One approach to targeting high-risk populations is to identify individuals who are genetically predisposed to gastric cancer, as up to 15% of all patients report family history of the disease. On the basis of clinical manifestations, three gastric cancer syndromes have been described, but the diagnosis of some of these syndromes is suboptimal and could benefit from genetic information. Over the past decade, genome-wide association and next-generation sequencing studies have identified several low penetrance variants and high-risk genes, considerably increasing our understanding of inherited gastric cancer predisposition. From these studies, PALB2 has emerged as a new familial gastric cancer gene. Furthermore, genetic analyses in patients with sporadic gastric cancer suggest that more than 10% of all cases have pathogenic mutations, a finding of great importance for cancer aetiology. In this Review, we summarise the role of genetics in gastric cancer aetiology and the implications of genetics findings for the prevention of this malignancy.

Donenberg T, George S, Ali J, et al.
A clinically structured and partnered approach to genetic testing in Trinidadian women with breast cancer and their families.
Breast Cancer Res Treat. 2019; 174(2):469-477 [PubMed] Related Publications
INTRODUCTION: Breast cancer (BC) is the leading cause of cancer death in Caribbean women. Across the Caribbean islands, the prevalence of hereditary breast cancer among unselected breast cancer patients ranges from 5 to 25%. Moreover, the prevalence of BC among younger women and the high mortality in the Caribbean region are notable. This BC burden presents an opportunity for cancer prevention and control that begins with genetic testing among high-risk women. Measured response to positive genetic test results includes the number of preventive procedures and cascade testing in family members. We previously reported data on an active approach to promote cascade testing in the Bahamas and report on preventive procedures showing moderate uptake. Here, we describe a clinically structured and community-partnered approach to the dissemination and follow-up of genetic test results including family counseling for the promotion of risk mitigation strategies and cascade testing in our Trinidadian cohort of patients tested positive for BC predisposition genes.
METHODS: As a part of our initial study of BC genetic testing in Trinidad and Tobago, all participants received pre-test counseling including three-generation pedigree and genetic testing for BRCA1/2, PALB2, and RAD51C. The study was approved by the University of Miami IRB and the Ethics Committee of the Ministry of Health, Trinidad and Tobago. We prospectively evaluated a clinically structured approach to genetic counseling and follow-up of BC mutation carriers in Trinidad and Tobago in 2015. The intervention consisted of (1) engaging twenty-nine BC patients with a deleterious gene mutation (probands), and (2) invitation of their at-risk relatives to attend to a family counseling session. The session included information on the meaning of their results, risk of inheritance, risk of cancer, risk-reduction options, offering of cascade testing to family members, and follow-up of proband decision-making over two years.
RESULTS: Twenty-four of twenty-nine mutation carriers (82.8%) consented to enroll in the study. At initial pedigree review, we identified 125 at-risk relatives (ARR). Seventy-seven ARR (62%) attended the family counseling sessions; of these, 76 ARR (99%) consented to be tested for their family gene mutation. Genetic sequencing revealed that of the 76 tested, 35 (46%) ARR were carriers of their family mutation. The ARR received their results and were urged to take preventative measures at post-test counseling. At 2-year follow-up, 6 of 21 probands with intact breasts elected to pursue preventive mastectomy (28.5%) and 4 of 20 women with intact ovaries underwent RRSO (20%).
CONCLUSIONS: In Trinidad and Tobago, a clinically structured and partnered approach to our testing program led to a significant rate of proband response by completing the intervention counseling session, executing risk-reducing procedures as well as informing and motivating at-risk relatives, thereby demonstrating the utility and efficacy of this BC control program.

Wu Y, Dong X, Wang Y, et al.
Association between rs120963, rs152451, rs249935, rs447529, rs8053188, and rs16940342 Polymorphisms in the PALB2 Gene and Breast Cancer Susceptibility: A Meta-Analysis.
Oncol Res Treat. 2018; 41(12):780-786 [PubMed] Related Publications
BACKGROUND: The aim of this study was to explore the association between single nucleotide polymorphisms (SNPs) in the rs120963, rs152451, rs249935, rs447529, rs8053188, and rs16940342 loci in the PALB2 gene and breast cancer risk.
METHODS: Studies investigating the association between SNPs in the PALB2 gene and breast cancer susceptibility were retrieved from the PubMed, Embase, Web of Science, CNKI (Chinese National Knowledge Infrastructure), WanFang, and CBM (China Biology Medicine) databases. Eligible studies were screened according to inclusion/exclusion criteria and principles of quality evaluation. Meta-analysis was performed using Stata 14.0 software. Odds ratios with their corresponding 95% confidence intervals were pooled to assess the association between SNPs in the PALB2 gene loci rs249935, rs447529, rs8053188, rs16940342, rs152451, and rs120963 and breast cancer susceptibility.
RESULTS: A total of 9 case-control studies were eligible for this meta-analysis. SNPs in the PALB2 gene loci rs120963, rs249935, and rs447529 were significantly associated with an increased or decreased risk of breast cancer. No significant association was detected for rs152451, rs8053188, and rs16940342 under 4 genetic models.
CONCLUSION: The results of this study suggest that SNPs in the PALB2 loci rs120963/rs249935/rs447529, but not in the other 3 loci (rs152451/rs8053188/rs16940342), may contribute to breast cancer susceptibility.

Dianatpour A, Faramarzi S, Ghafouri-Fard S
Meta-Analysis of Association between PALB2 Polymorphisms and Breast Cancer
Asian Pac J Cancer Prev. 2018; 19(10):2897-2903 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Background: Previous studies have assessed associations between single nucleotide polymorphisms (SNPs) of the Partner and localizer of BRCA2 (PALB2) gene and risk of breast cancer. However, the results of these studies are not consistent. Materials and Methods: We designed a meta-analysis to obtain a more reliable appraisal of the association between SNPs in the PALB2 gene and the susceptibility to breast cancer. We searched PubMed, Google scholar and Embase databases and selected six studies with sufficient data to estimate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Results: Statistical analyses showed that the rs120963 was associated with breast cancer risk in allelic (OR (95% CI) = 1.33 (1.18-1.49)), homozygous (OR (95% CI) = 1.74 (1.31-2.32)), dominant (OR (95% CI) = 1.42 (1.22, 1.65)) and recessive (OR (95% CI) = 1.54 (1.17, 2.03)) models. The rs249954 and rs16940342 were associated with breast cancer risk in allelic (OR (95% CI) = 1.13 (1.04, 1.23) and 1.12 (1.01, 1.24) respectively) and dominant (OR (95% CI) = 1.23 (1.09, 1.39) and 1.18 (1.04, 1.33) respectively) models. The rs249935 and rs447529 SNPs were associated with breast cancer in homozygous (OR (95% CI) = 0.67 (0.46, 0.97) and 0.51 (0.30, 0.89) respectively) and recessive (OR (95% CI) = 0.65 (0.45, 0.95) and 0.51 (0.30, 0.88) respectively) models. Conclusions: The current meta-analysis shows the associations between five SNPs of PALB2 and breast cancer risk and confirms the results of previous studies regarding the role of this gene in the pathogenesis of breast cancer

Simhadri S, Vincelli G, Huo Y, et al.
PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response.
Oncogene. 2019; 38(10):1585-1596 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The G2/M checkpoint inhibits mitotic entry upon DNA damage, thereby preventing segregation of broken chromosomes and preserving genome stability. The tumor suppressor proteins BRCA1, PALB2 and BRCA2 constitute a BRCA1-PALB2-BRCA2 axis that is essential for homologous recombination (HR)-based DNA doublestrand break repair. Besides HR, BRCA1 has been implicated in both the initial activation and the maintenance of the G2/M checkpoint, while BRCA2 and PALB2 have been shown to be critical for its maintenance. Here we show that all three proteins can play a significant role in both checkpoint activation and checkpoint maintenance, depending on cell type and context, and that PALB2 links BRCA1 and BRCA2 in the checkpoint response. The BRCA1-PALB2 interaction can be important for checkpoint activation, whereas the PALB2-BRCA2 complex formation appears to be more critical for checkpoint maintenance. Interestingly, the function of PALB2 in checkpoint response appears to be independent of CHK1 and CHK2 phosphorylation. Following ionizing radiation, cells with disengaged BRCA1-PALB2 interaction show greatly increased chromosomal abnormalities due apparently to combined defects in HR and checkpoint control. These findings provide new insights into DNA damage checkpoint control and further underscore the critical importance of the proper cooperation of the BRCA and PALB2 proteins in genome maintenance.

Yang C, Ceyhan-Birsoy O, Mandelker D, et al.
A synonymous germline variant PALB2 c.18G>T (p.Gly6=) disrupts normal splicing in a family with pancreatic and breast cancers.
Breast Cancer Res Treat. 2019; 173(1):79-86 [PubMed] Related Publications
PURPOSE: Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 synonymous variant c.18G>T (p.Gly6=) identified in a family with pancreatic and breast cancers.
METHODS: The PALB2 c.18G>T (p.Gly6=) variant in this family was identified using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT™). RT-PCR and subsequent cloning were performed to investigate whether this variant affects normal splicing.
RESULTS: This variant completely disrupts normal splicing and leads to several abnormal transcripts, which presumably leads to premature protein truncation. The major abnormal transcript resulted in a deletion of 32 base pairs in exon 1 and frameshift.
CONCLUSIONS: Our results indicate that the PALB2 c.18G>T (p.Gly6=) variant is likely pathogenic. This study provided important laboratory evidence for classification of this variant and guided improved patient management.

Richardson ME, Chong H, Mu W, et al.
DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes.
Genet Med. 2019; 21(3):683-693 [PubMed] Related Publications
PURPOSE: Gross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications.
METHODS: The DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2.
RESULTS: DBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic.
CONCLUSION: DBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.

Dong L, Wu N, Wang S, et al.
Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing.
Hum Mutat. 2018; 39(10):1442-1455 [PubMed] Related Publications
In this study, a customized amplicon-based target sequencing panel was designed to enrich the whole exon regions of six genes associated with the risk of breast cancer. Targeted next-generation sequencing (NGS) was performed for 146 breast cancer patients (BC), 71 healthy women with a family history of breast cancer (high risk), and 55 healthy women without a family history of cancer (control). Sixteen possible disease-causing mutations on four genes were identified in 20 samples. The percentages of possible disease-causing mutation carriers in the BC group (8.9%) and in the high-risk group (8.5%) were higher than that in the control group (1.8%). The BRCA1 possible disease-causing mutation group had a higher prevalence in family history and triple-negative breast cancer, while the BRCA2 possible disease-causing mutation group was younger and more likely to develop axillary lymph node metastasis (P < 0.05). Among the 146 patients, 47 with a family history of breast cancer were also sequenced with another 14 moderate-risk genes. Three additional possible disease-causing mutations were found on PALB2, CHEK2, and PMS2 genes, respectively. The results demonstrate that the six-gene targeted NGS panel may provide an approach to assess the genetic risk of breast cancer and predict the clinical prognosis of breast cancer patients.

Castéra L, Harter V, Muller E, et al.
Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families.
Genet Med. 2018; 20(12):1677-1686 [PubMed] Related Publications
PURPOSE: Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.
METHODS: Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.
RESULTS: Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01-17.22], 8.61 [6.78-10.82], 8.22 [4.91-13.05], 4.54 [2.55-7.48], 5.23 [1.46-13.17], 3.20 [2.14-4.53], 2.49 [1.42-3.97], 1.67 [1.18-2.27], and 2.50 [1.12-4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78-19.59], 12.44 [2.94-33.30] and 3.82 [1.66-7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48-34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37-25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.
CONCLUSION: Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.

Rescigno P, Chandler R, de Bono J
Relevance of poly (ADP-ribose) polymerase inhibitors in prostate cancer.
Curr Opin Support Palliat Care. 2018; 12(3):339-343 [PubMed] Related Publications
PURPOSE OF REVIEW: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved drugs for the treatment of ovarian and breast cancer and currently under investigation for the treatment of prostate cancer and other malignancies with aberrations in homologous recombination DNA repair.This review summarizes literature published during 2017 concerning the relevance of PARPi in prostate cancer and presents new evidence on mechanisms of resistance and biomarkers of response.
RECENT FINDINGS: The approval of several PARPi (olaparib, rucaparib, and niraparib) has driven the focus of anticancer treatment on synthetic lethality in prostate cancer too. Despite anecdotal reports of long-term responders, most cancers become resistant to these therapies.Different mechanisms of primary and acquired resistance to PARPi have been recently investigated including loss of PARP1 expression, BRCA mutations with partial function, and acquisition of reversion restoration of function mutations.
SUMMARY: Here, we discuss the importance of PARPi in metastatic castration-resistant prostate cancer and discuss the possible mechanisms of resistance.

Maifrede S, Nieborowska-Skorska M, Sullivan-Reed K, et al.
Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors.
Blood. 2018; 132(1):67-77 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Mutations in FMS-like tyrosine kinase 3 (FLT3), such as internal tandem duplications (ITDs), can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i's), which are rarely curative. PARP1 inhibitors (PARP1i's) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency. We show here that inhibition of FLT3(ITD) activity by the FLT3i AC220 caused downregulation of DNA repair proteins BRCA1, BRCA2, PALB2, RAD51, and LIG4, resulting in inhibition of 2 major DNA double-strand break (DSB) repair pathways, HR, and nonhomologous end-joining. PARP1i, olaparib, and BMN673 caused accumulation of lethal DSBs and cell death in AC220-treated FLT3(ITD)-positive leukemia cells, thus mimicking synthetic lethality. Moreover, the combination of FLT3i and PARP1i eliminated FLT3(ITD)-positive quiescent and proliferating leukemia stem cells, as well as leukemic progenitors, from human and mouse leukemia samples. Notably, the combination of AC220 and BMN673 significantly delayed disease onset and effectively reduced leukemia-initiating cells in an FLT3(ITD)-positive primary AML xenograft mouse model. In conclusion, we postulate that FLT3i-induced deficiencies in DSB repair pathways sensitize FLT3(ITD)-positive AML cells to synthetic lethality triggered by PARP1i's. Therefore, FLT3(ITD) could be used as a precision medicine marker for identifying AML patients that may benefit from a therapeutic regimen combining FLT3 and PARP1i's.

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