Non-Infectious Morbidity during Pediatric Acute Myeloid Leukemia Chemotherapy in the Netherlands: A 15-Year Overview

Abstract Introduction Together with considerable improvement in diagnostics and supportive care measures, treatment intensification has contributed to the improvement of pediatric acute myeloid leukemia (AML) survival outcomes. However, treatment-related toxicity is a consequence of intensified chemotherapy regimens, which has profound implications for both morbidity and mortality. Despite the known devastating impact of all types of toxicity on quality of life (QoL), studies presenting the different forms of non-infectious toxicity prevalent during the most recent Dutch pediatric AML protocols are lacking given that only prior protocols have been evaluated in this manner as of yet. Furthermore, the literature on non-infectious toxicity incidence in pediatric AML patients is relatively scarce. Therefore, the objectives of this study were to: 1) evaluate the cumulative incidence (C.I.) of severe, but non-lethal, non-infectious toxicity during AML treatment according to the last three consecutive protocols of the Dutch Childhood Oncology Group (DCOG), and 2) compare treatment-related toxicity frequencies between protocols. Methods A retrospective chart review was performed on 245 Dutch patients diagnosed with de novo AML (acute promyelocytic leukemia, myeloid leukemia of Down Syndrome, and secondary AML were excluded) and treated according to ANLL-97/AML-12 (1998-2005) n=118, AML-15 (2005-2010) n=60, or DB-AML-01 (2010-2013) n=67. Table 1 details protocol specifics, including drug dosages per course. Grade 3-4 toxicities, including hematological toxicity, cardiotoxicity, respiratory toxicity, mucositis, typhlitis, nephrotoxicity, hepatotoxicity, neurotoxicity, pain, allergic anaphylactic reaction, and elevation of alanineaminotransferase or bilirubin were defined according to Common Terminology Criteria for Adverse Event version 4.0, excluding infectious toxicity. Grade 5 toxicity (treatment-related mortality) was beyond the scope of this study. Intensive care unit (ICU) admission data was additionally assessed. Toxicity C.I.s were determined via competing events analyses. Relapse and death were considered competing events. Patients were censored at time of stem cell transplantation. Per-protocol comparisons were conducted via Chi-square test, due to lack of sufficient power required to calculate C.I.s. Results Median age at diagnosis was 6.0 years [interquartile range (IQR) 1.0-12.0], 58% were male. Mucositis was the most frequent form of non-hematological toxicity with a C.I. of 86.1% (standard error (S.E.) 3.5%), followed by hepatotoxicity (C.I. 27.4%, S.E. 2.9%), and respiratory toxicity (C.I. 24.6%, S.E. 3.0%) (Table 2). Eighty-three patients (C.I. 33.9%, S.E. 3.0%) were admitted to the ICU at least once, for a median of 6.0 days [IQR 2.0-15.0] (Table 2). Relatively more blood transfusions (both erythrocyte and thrombocyte) were administered to patients treated according to AML-15 (98.3%) and DB-AML-01 (97.0%) compared to AML-12 (86.4%) (p=0.01 and p=0.02, respectively). Relatively more patients suffered from severe mucositis during DB-AML-01 compared to AML-12 (43.4% vs. 25.4%, p=0.01). More patients treated according to AML-15 had bilirubin levels >3x upper limit of normal (ULN) compared to those treated according to AML-12 (13.3% vs. 3.4%, p=0.01). There were no differences in non-infectious toxicity frequency between AML-15 and DB-AML-01. Other forms of toxicity did not differ significantly between protocols. The percentage of patients admitted to the ICU at least once during treatment was 33.9% in AML-12, 26.7% in AML-15, and 40.3% in DB-AML-01. Conclusions The high incidence of severe short- and long-term toxicities during pediatric AML therapy poses substantial challenges for patients, families, and care providers. Mucositis was the most common form of non-hematological, non-infectious toxicity in the whole cohort and across all Dutch protocols. Toxicities were more prevalent during the more recent protocols (AML-15 and DB-AML-01) compared to AML-12. Therefore, our findings are important in that they substantiate the need to optimize pediatric AML care in a manner which decreases treatment-related toxicity and QoL impairment. High treatment-related morbidity rates stress the urge to improve supportive care and develop less toxic treatment, while maintaining efficacy. Figure 1 Figure 1. Disclosures Zwaan: Sanofi: Consultancy.

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An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

Journal of Oncology ◽

10.1155/2021/5550116 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Feng Jiang ◽

Xin-Yu Wang ◽

Ming-Yan Wang ◽

Yan Mao ◽

Xiao-Lin Miao ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Immune Checkpoint ◽

Myeloid Leukemia ◽

Immune Cell ◽

Cox Regression ◽

Secondary Data ◽

Gene Signature ◽

Pediatric Acute Myeloid Leukemia ◽

Pediatric Aml ◽

Acute Myeloid

Objective. The aim of this research was to create a new genetic signature of immune checkpoint-associated genes as a prognostic method for pediatric acute myeloid leukemia (AML). Methods. Transcriptome profiles and clinical follow-up details were obtained in Therapeutically Applicable Research to Generate Effective Treatments (TARGET), a database of pediatric tumors. Secondary data was collected from the Gene Expression Omnibus (GEO) to test the observations. In univariate Cox regression and multivariate Cox regression studies, the expression of immune checkpoint-related genes was studied. A three-mRNA signature was developed for predicting pediatric AML patient survival. Furthermore, the GEO cohort was used to confirm the reliability. A bioinformatics method was utilized to identify the diagnostic and prognostic value. Results. A three-gene (STAT1, BATF, EML4) signature was developed to identify patients into two danger categories depending on their OS. A multivariate regression study showed that the immune checkpoint-related signature (STAT1, BATF, EML4) was an independent indicator of pediatric AML. By immune cell subtypes analyses, the signature was correlated with multiple subtypes of immune cells. Conclusion. In summary, our three-gene signature can be a useful tool to predict the OS in AML patients.

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Acute Differentiated Dendritic Cell Leukemia: A New Form of Pediatric Acute Myeloid Leukemia (AML) with MLL Translocations.

Blood ◽

10.1182/blood.v106.11.3263.3263 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3263-3263

Author(s):

Luca Lo Nigro ◽

Laura Sainati ◽

Anna Leszl ◽

Elena Mirabile ◽

Monica Spinelli ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Dendritic Cells ◽

Dendritic Cell ◽

Myeloid Leukemia ◽

Fusion Transcript ◽

Fish Analysis ◽

Rt Pcr ◽

Pediatric Acute Myeloid Leukemia ◽

Pediatric Aml ◽

Acute Myeloid

Abstract Background: Myelomonocytic precursors from acute or chronic leukemias can differentiate to dendritic cells in vitro, but leukemias with a dendritic cell immunophenotype are rare, have been reported mainly in adults, and their molecular pathogenesis is unknown. Dendritic cells are classified as Langherans, myeloid and lymphoid/plasmacytoid cells, but leukemias arising from dendritic cells are unclassified in the FAB system. We identified a new entity of pediatric acute myeloid leukemia (AML) presenting with morphologic and immunophenotypic features of mature dendritic cells, which is characterized by MLL gene translocation. Methods and Results: Standard methods were used to characterize the morphology, immunophenotype, karyotype and MLL translocations in 3 cases of pediatric AML. The patients included two boys and one girl diagnosed with AML between 1–6 years old. Their clinical histories and findings included fever, pallor, abdominal and joint pain, adenopathy, hepatosplenomegaly, normal WBC counts but anemia and thrombocytopenia. and no evidence of CNS disease. The bone marrow aspirates were hypocellular and replaced completely by large blasts with irregular nuclei, slightly basophilic cytoplasm, and prominent cytoplasmic projections. There were no cytoplasmatic granules or phagocytosis. Myeloperoxidase and alpha napthyl esterase reactions were negative, excluding FAB M5 AML, and the morphology was not consistent with any standard FAB morphologic diagnosis. The leukemic blasts in all three cases were CD83+, CD86+, CD116+, consistent with differentiated myeloid dendritic cells, and did not express CD34, CD56 or CD117. MLL translocations were identified in all 3 cases. In the first case FISH analysis showed t(10;11)(p12;q23) and RT-PCR identified and a ‘5-MLL-AF10-3’ fusion transcript. In the second case FISH analysis showed t(9;11)(p22;q23) and RT-PCR identified and a ‘5-MLL-AF9-3’ fusion transcript. In the remaining case, the MLL gene rearrangement was identified by Southern blot analysis and RT-PCR showed an MLL-AF9 fusion transcript. The fusion transcripts in all 3 cases were in-frame. Remission induction was achieved with intensive chemotherapy, and all three patients have remained in durable remission for 30–60 months after hematopoietic stem cell transplantation. Conclusions. We have characterized a new pediatric AML entity with features of mature dendritic cells, MLL translocation and an apparently favorable prognosis. The in-frame MLL fusion transcripts suggest that chimeric MLL oncoproteins underlie its pathogenesis. The partner genes in all 3 cases were known partner genes of MLL that encode transcription factors. This study increases the spectrum of leukemias with MLL translocations. Comprehensive morphological, immunophenotypic, cytogenetic and molecular analyses are critical for this diagnosis, and will reveal its frequency and spectrum as additional cases are uncovered.

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In Vivo Evaluation of Mesothelin As a Therapeutic Target in Pediatric Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-123794 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1370-1370 ◽

Cited By ~ 1

Author(s):

Anilkumar Gopalakrishnapillai ◽

Allison Kaeding ◽

Christoph Schatz ◽

Anette Sommer ◽

Soheil Meshinchi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Combination Therapy ◽

Therapeutic Target ◽

Myeloid Leukemia ◽

Antibody Drug Conjugate ◽

Pediatric Acute Myeloid Leukemia ◽

Pediatric Aml ◽

Acute Myeloid ◽

Antibody Drug

Pediatric acute myeloid leukemia (AML) continues to have a cure rate of only 50% despite the use of highly intensive cytotoxic chemotherapy. Transcriptome sequencing of several AML samples by the NCI/COG TARGET AML Initiative identified mesothelin (MSLN) to be highly overexpressed in about one-third of pediatric AML (Tarlock et al., Blood, 128:2873, 2016). Because MSLN is not expressed in normal bone marrow samples (Fan et al., Blood, 130:3792, 2017) and only to a low level in other human organs and tissues, MSLN is an attractive therapeutic target for pediatric AML (Kaeding et al., Blood, 130:2641, 2017). The anti-MSLN antibody-drug conjugate (ADC) anetumab ravtansine (BAY 94-9343) generated by conjugating MSLN-antibody with tubulin inhibitor DM4 (Meso-ADC), and isotype control antibody conjugated with the same drug (Iso-ADC) were used to evaluate the efficacy of MSLN targeting in vivo. MSLN-overexpressing K562 (K562-MSLN) CML cells and MV4;11 (MV4;11-MSLN) AML cells were generated by lentiviral transduction of MSLN cDNA. Cell line-derived xenografts (CDX) were created by injecting the MSLN-transduced or parental (MSLN-) cells into NSG-SGM3 mice via the tail vein. Mice were randomly assigned to treatment groups when the median percentage of human cells in mouse peripheral blood was greater than 0.5%. K562-MSLN CDX mice treated with Meso-ADC (5 mg/Kg Q3dx3, i.v.) survived a median of 46 days longer than those treated with Iso-ADC (P=0.0011) and significantly longer than comparison groups, including K562-MSLN CDX mice treated with daunorubicin and Ara-C (DA, P=0.0008) or untreated (P=0.0018) (Fig. 1A). Median survival of K562 CDX mice treated with Meso-ADC, Iso-ADC, or untreated was similar (Fig. 1B). MV4;11-MSLN CDX mice treated with Meso-ADC exhibited complete remission and remained disease-free at 1 year post cell injection, with AML cell burden remaining <0.1% throughout the study period (Fig. 1C). In contrast, MV;11-MSLN CDX mice treated with Iso-ADC or untreated succumbed to disease at 72 and 38 days, respectively. Taken together, these results indicate that Meso-ADC was efficacious in reducing leukemia burden, and this effect required MSLN expression in target cells. We have generated a panel of patient-derived xenograft (PDX) lines by transplanting and serially propagating primary pediatric AML samples into NSG-SGM3 mice. The efficacy of Meso-ADC was also evaluated in a systemic PDX model using a MSLN+ PDX line (NTPL-146). NTPL-146 PDX mice treated with Meso-ADC (5 mg/Kg, Q3dx3 -x2 cycles) survived a median of 50 days longer than those treated with Iso-ADC (P=0.0018, Fig. 1D, arrows indicate time when each treatment cycle was initiated). In an independent experiment with NTPL-146 PDX mice, a survival benefit of Meso-ADC treatment over no treatment was observed after 1 cycle of Meso-ADC treatment (5 mg/Kg, Q3dx3, P=0.0019, Fig. 1E). Additionally, a combination therapy strategy with daunorubicin and Ara-C followed by Meso-ADC (DA -> Meso-ADC) resulted in improved median survival over Meso-ADC (P=0.0027) or DA treatment alone (P=0.0018) (Fig. 1E). The disseminated MSLN+ leukemia mouse models described herein support MSLN-targeted antibody-drug conjugate as a potential treatment strategy in MSLN+ AML. Furthermore, we provide the first in vivo demonstration of synergy between MSLN-targeted therapy and conventional chemotherapy in MSLN+ AML, warranting additional investigation to validate and optimize novel strategies for combination therapy. Figure 1 Disclosures Kaeding: Celgene: Employment. Schatz:Bayer AG: Employment. Sommer:Bayer AG: Employment, Equity Ownership.

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Identification of Gene Expression Signatures Accurately Predicting Cytogenetic Subtypes in Pediatric Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v112.11.1509.1509 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1509-1509 ◽

Cited By ~ 1

Author(s):

Brian V Balgobind ◽

Marry M van den Heuvel-Eibrink ◽

Renee X Menezes ◽

Dirk Reinhardt ◽

Iris H.I.M. Hollink ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Type I ◽

Pediatric Acute Myeloid Leukemia ◽

Genetic Aberrations ◽

Gene Expression Signatures ◽

Pediatric Aml ◽

Normal Cytogenetics ◽

Acute Myeloid

Abstract Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, which is classified according to the WHO classification, based on morphology, immunophenotyping and non-random genetic aberrations. AML is hypothesized to arise from two different types of genetic aberrations, i.e. type-I (proliferation enhancing) mutations and type-II (differentiation impairing) mutations. To detect genetic aberrations multiple techniques such as conventional karyotyping, FISH and RT-PCR are being used. In addition to conventional karyotyping, the latter two techniques revealed a higher frequency of aberrations. Still, failures or false negative results should be taken into account. Recent studies have focused on the potential of gene expression profiling (GEP) to classify acute leukemias. To study the clinical value of classification by GEP, we first used a double-loop cross validation (CV) to avoid over-fitting of GEP data and, subsequently, addressed whether the identified GEP was suitable to classify pediatric AML cases in a second independent group of cases. Affymetrix Human Genome U133 plus 2.0 microarrays were used to generate gene expression profiles of 257 children with AML, with high blast counts, if necessary, after enrichment (~80% or more) and good quality RNA. Probe set intensities were normalized using the variance-stabilizing normalization (VSN) implemented in R (version 2.2.0). The patient group was divided into a test cohort (n=170) and an independent validation cohort (n=87). The test cohort was used to construct the classifier using two levels of CV: the minimum number of predictive genes was estimated using a 10-fold CV on random subsets of about 113 (~2/3 of total) patients; the accuracy of the obtained classifier is estimated on the remaining 57 (~1/3) patients. Candidate genes to represent the GEP in the classifier were those genes that discriminated AML subtypes according to an empirical Bayes linear regression model (Bioconductor package: Limma). To construct a reliable classifier it was sufficient to use 75 probe sets, representing the top 15 discriminating probe sets for MLL-gene rearranged AML, t(8;21), inv(16), t(15;17) and t(7;12). These subtypes represented ~50% of the included patients. The remaining patients either had normal cytogenetics, random aberrations or no data available (cytogenetic failure). Due to the heterogeneity of these remaining groups discriminative probe sets were not found. This classifier could reliably predict the 5 subtypes with a median accuracy of 93%. Validation of the classifier on the independent cohort confirmed that the sensitivity and accuracy was more than 99%. No gene expression signatures could be found for the molecular aberrations NPM1, CEBPa, MLL-PTD, FLT3, C-KIT, RAS or PTPN1, possibly due to the small number of cases. However, specific gene expression signatures were found for FLT3-ITD within the subset of cases with t(15;17) or normal cytogenetics. Importantly, a high expression of HOXB-cluster related genes was found in cases with FLT3-ITD and normal cytogenetics. In conclusion, GEP can correctly predict several important cytogenetic subtypes of pediatric AML, including cases that are currently classified using different cytogenetic techniques and cases with failed cytogenetic analysis. Prospective studies are needed to validate the use of GEP in the classification of pediatric AML, especially to provide information on its utility in clinical practice. Increasing numbers in rare subtypes may result in the discovery of genes discriminative for them, and may foster GEP as a new diagnostic tool.

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BCOR and BCORL1 Mutations In Pediatric Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.3815.3815 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3815-3815

Author(s):

Malou C.H. Hermkens ◽

Marry M. van den Heuvel-Eibrink ◽

Susan T.J.C.M. Arentsen-Peters ◽

Maarten W.J. Fornerod ◽

Andre Baruchel ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Genetic Background ◽

Myeloid Leukemia ◽

Disease Outcome ◽

Next Generation ◽

Genetic Syndrome ◽

Pediatric Acute Myeloid Leukemia ◽

Exon 4 ◽

Pediatric Aml ◽

Acute Myeloid

Abstract Introduction In pediatric acute myeloid leukemia (AML) current survival rates are approximately 70%, but further improvements are required to improve disease outcome. Prognosis is correlated to early response to treatment and genetic aberrations (Creutzig et al, 2012). In approximately 20% no cytogenetic aberrations can be identified. In some of these cases repetitive aberrations, such as NPM1 mutations or cryptic translocations including NUP98-translocations (Hollink, 2011 and De Rooij, 2013) have been found. Recently, mutations in BCOR and BCORL1, both located on the X-chromosome, were found in adult AML using next generation sequencing. They both are transcriptional co-repressors, although with distinct binding targets (Tiacci, Heamatologica, 2012), and are thought to represent a novel mechanism of leukemogenesis. Somatic inactivating BCOR mutations were identified in 4% of adult cytogenetically normal (CN-) AML patients, predominantly located in exon 4, but also in other exons (Grossmann et al, 2011). Of interest, germline BCOR mutations cause the X-linked oculo-facio-cardio-dental genetic syndrome, which may occur due to its function as a co-repressor of the BCL6 gene. Somatic inactivating BCORL1mutations were found in 6% of adult AML patients (Li et al, 2011); all mutations were located in exon 4. Their exact role in AML and the targets of their co-repressive transcriptional activity has not been elucidated as yet (Tiacci, Haematologica, 2012). Methods We screened newly diagnosed pediatric AML patients for the presence of BCOR and BCORL1 mutations using direct sequencing of the complete coding sequence of both genes starting with a cohort of 86 patients including all cytogenetic subgroups patients, and later expanding this with an additional 146 patients for BCORL1screening of exon 4. This cohort was enriched for samples from CN-AML patients (56% and 21% respectively). Samples were obtained from the Dutch Childhood Oncology Group (DCOG; The Hague, The Netherlands), the AML-BFM-SG; Hannover, Germany and Prague, Czech Republic, and the Hôpital Robert Debré (Paris, France). Results A single BCOR mutation was found in 1 patient only with CN-AML. The mutation, p.A854T, was located in exon 4. The patient was a 4 year old boy with a FAB M1, WBC 354 x 109/L, who is alive 45 months after diagnosis. In addition, only 1 patient carried a BCORL1 mutation. The mutation, located in exon 4, p.G158X, caused a premature stop-codon. The male patient was diagnosed with secondary AML, aged 17 years, with normal cytogenetics and a WBC of 9.4 x 109/L, FAB M1, and died 3 months after diagnosis. Multiple recurrent SNPs were observed for both BCOR (rs5917933: 7/86 pts (91.9%); rs6520618: 15/86 (17.4%); rs144606152: 6/86 (7.0%)) and BCORL1 (rs4830173: 232/232 (100%); rs5932715: 36/232 (15.5%)), all in exon 4. No relation could be found between the presence of SNPs and disease outcome. Conclusions BCOR and BCORL1 mutations occur in less than 1% of pediatric AML patients. These data provide further evidence for the differences in genetic background between pediatric and adult AML. Separate next-generation studies should be performed to elucidate the genetic background of pediatric CN-AML. This project was funded by KIKA, project number 64, entitled: Aberrant signal transduction profiling in pediatric AML. Disclosures: No relevant conflicts of interest to declare.

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Pediatric acute myeloid leukemia with t(8;21) variant: what is the value on clinical outcome?

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20173806 ◽

2017 ◽

Vol 4 (5) ◽

pp. 1890

Author(s):

Juliana C. Abreu ◽

Raissa M. Fontes ◽

Jesamar C. Matos ◽

Fátima G. Jorge ◽

Diego S. Lima

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Clonal Expansion ◽

Pediatric Acute Myeloid Leukemia ◽

Favorable Prognosis ◽

Structural Abnormalities ◽

Pediatric Aml ◽

Acute Myeloid

Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors that results in the bone marrow (BM) failure. Some cytogenetic alterations can be used to predict the prognosis of the disease. AML with t(8;21), presenting RUNX1/RUNX1T1 gene fusion, is associated to favorable prognosis and it is one of most prevalent structural abnormalities in pediatric AML. Variants of t(8;21) has been described, though the prognostic value of these changes remains controversial, especially in pediatric patients. Thereby, we report a pediatric patient with AML with RUNX1/RUNX1T1 fusion presenting the variant t(1;21;8). The diagnosis was confirmed by myelogram, immunophenotyping, cytogenetics and molecular biology. After the diagnosis, the patient was subjected to chemotherapy and submitted to related allogeneic BM transplant. Until this date, the patient has no clinical complaints, predicting a favorable outcome. The register of variants and its proper follow up contributes to a better understanding of the mechanisms involved in these rearrangements and provides information that may be relevant for an appropriate classification and risk stratification of these patients.

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Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia

Cancers ◽

10.3390/cancers13194817 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4817

Author(s):

Lina Marie Hoffmeister ◽

Eser Orhan ◽

Christiane Walter ◽

Naghmeh Niktoreh ◽

Helmut Hanenberg ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Impact ◽

Kras Mutations ◽

Pediatric Acute Myeloid Leukemia ◽

Younger Age ◽

Structural Aberrations ◽

Pediatric Aml ◽

Acute Myeloid

KMT2A rearrangements (KMT2A-r) are among the most common structural aberrations in pediatric acute myeloid leukemia (AML) and are very important for the risk group stratification of patients. Here, we report the outcome of 967 pediatric AML patients with a known KMT2A-r status. The large cohort was characterized by morphology, multicolor flow cytometry, classical cytogenetics and mutation analysis via panel sequencing. In total, the blasts of 241 patients (24.9%) showed KMT2A-r. KMT2A-r is associated with FAB M5, a high white blood cell count and younger age at diagnosis. When subgroups were combined, KMT2A-r had no impact on event-free survival (EFS) and overall survival (OS); however, various subgroups showed a different prognosis, ranging from a <50% OS for KMT2A/AFDN (n = 11) to a 100% chance of survival for patients harboring the rare translocation KMT2A/SEPTIN9 (n = 3, follow up of 3.7 to 9.6 years). A positive correlation of KMT2A-r with KRAS mutations (p < 0.001) existed, albeit without any prognostic impact. In addition, FLT3-ITDs were detected less frequently in AML with KMT2A-r (p < 0.001). Furthermore, KMT2A-r were mutually exclusive, with mutations in NPM1 (p = 0.002), KIT (p = 0.036), WT1 (p < 0.001) and CEBPA (p = 0.006), and translocations NUP98/NSD1 (p = 0.009), RUNX1/RUNX1T1 (p = 0.003) and CBFB/MYH11 (p = 0.006). In the 346 patients tested for CSPG4 expression, a correlation between CSPG4 expression and KMT2A-r was confirmed. However, CSPG4 expression also occurred in patients without KMT2A-r and had no significant prognostic impact on EFS and OS.

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A Role For a Multi-Drug Resistance Protein (MRP4/ABCC4) In Pediatric Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.2518.2518 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2518-2518

Author(s):

Shang Li Lian ◽

Yao WANG ◽

Sheng Zhou ◽

Mugdha Sukthankar ◽

Geoffrey A. Neale ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Abc Transporters ◽

Myeloid Leukemia ◽

Multi Drug Resistance ◽

Hematopoietic Stem ◽

Pediatric Acute Myeloid Leukemia ◽

Resistance Protein ◽

Pediatric Aml ◽

Acute Myeloid

Abstract Pediatric acute myeloid leukemia (AML) is an aggressive malignancy comprising 15-20% of childhood acute leukemias and remains a challenging disease with cure rates of only 60% using conventional therapy. However, unlike ALL de novo AML is characterized by a very low burden of genomic alterations suggesting other genetic and/or epigenetic alterations occur within hematopoietic stem cells (HSC) or progenitors to affect their normal self-renewal, proliferation and/or differentiation in this disease. Multi-drug Resistance Protein 4 (MRP4/ABCC4) is the fourth member of the ABCC subfamily of ABC transporters (de novoAML, suggesting MRP4 has a role in myeloid leukemia. Moreover, gene expression profiling from 155 pediatric AML patients showed that MRP4 was differentially expressed among AML subtypes with M7 having the highest expression. To characterize the function of MRP4 in normal hematopoiesis and in the etiology of AML, we use a murine Mrp4 knockout model. Mrp4KO mice had a similar number of BM progenitors as WT mice did. However, hematopoietic stem cells of Mrp4KO appeared to have an intrinsic defect because short- and long-term repopulation was impaired in a competitive repopulation (CR) mouse model. To examine the role of MRP4 in AML etiology, we generated an NMYC-overexpressing AML model because NMYC overexpression is a frequent event in pediatric AML and is highly oncogenic in mouse myeloid cells (Kawagoe et al., 2007). In addition, NMYC expression was frequently associated with elevated MRP4 expression, a recently reported target of NMYC (Porro et al., 2010; Porro et al., 2011). We showed that NMYC-overexpressing WT BM cell had an increased progenitor population, which was absent in Mrp4KO cells. Because overexpression of MRP4 in lineage-depleted bone marrow cells increased the CD34+ population which correlated with increased expression of progenitor marker such as cKit, we tested whether exogenous MRP4 could rescue the progenitor population in Mrp4KO. We demonstrated that restoring MRP4 in Mrp4KO cells indeed rescued the progenitor populations. Furthermore, Mrp4-deficiency delayed in vivo NMYC-dependent leukemogenesis in an AML mouse model, possibly by decreasing the proliferation/survival of the tumor cells. Current studies are further elucidating pathways whereby MRP4 provides a biological advantage. In summary, Mrp4 is important for both normal and deregulated progenitor functions, especially during leukemogenesis when progenitor populations greatly increase. It is likely MRP4 alters survival and/or proliferation of progenitors. This work will further our understanding of ABC transporters in the normal biology and pathology of hematopoietic cells and has the potential to facilitate identification of new therapeutic targets for AML treatment. This work was supported by NIH and by the American Lebanese Syrian Associated Charities (ALSAC). † Shang Li Lian, PhD [email protected], 901-595-2782, address: Chili’s Care Center, Rm I5206, Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. Disclosures: No relevant conflicts of interest to declare.

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