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Tanja Gruber, MD

  • Tanja Andrea Gruber
  • “Information is power. When families understand what you're doing and why, that helps us work together.”

It's important to me that patients have state-of-the-art care and a team that really cares about them. Its emotionally very difficult to have cancer or have a child with cancer, and we work hard to support patients and their families throughout the journey. It's very much a family affair.

Making sure the family and patient are informed is paramount, and I spend a lot of time explaining the treatment in detail. Information is power, and when families understand what you're doing and why, that helps us work together on decision-making. By the end of treatment, families often say to me, “I know so much, I could be a doctor.”

I want patients to look forward to coming to the clinic as much as I look forward to seeing them. It's a long journey, and I'm honored to be a part of their lives, standing beside them in the fight to beat cancer. Helping patients feel better and providing them with the best treatment available are my top priorities.

Trabajo y educación


University of Southern California, Los Angeles, CA, 05/16/2003

Últimos años de residencia

Children's Hospital Los Angeles Pediatric Residency, Los Angeles, CA, 06/30/2006


Childrens Hospital Los Angeles Hematology Oncology Fellowship, Los Angeles, CA, 07/31/2009

Certificado(s) de especialidad

Pediatric Hematology-Oncology, American Board of Pediatrics


Acute Myelogenous Leukemia

High-Risk Leukemia

Todo Publicaciones

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series. British journal of haematology Brivio, E., Chantrain, C. F., Gruber, T. A., Thano, A., Rialland, F., Contet, A., Elitzur, S., Dalla-Pozza, L., Kallay, K. M., Li, C., Kato, M., Markova, I., Schmiegelow, K., Bodmer, N., Breese, E. H., Hoogendijk, R., Pieters, R., Zwaan, C. M. 2021


No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n=9). The median dose in the first course was 1.74mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.

View details for DOI 10.1111/bjh.17333

View details for PubMedID 33529389

Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia. Leukemia Goemans, B. F., Noort, S., Blink, M., Wang, Y., Peters, S. T., van Wouwe, J. P., Kaspers, G., de Haas, V., Kollen, W. J., van der Velden, V. H., Gruber, T. A., Zwaan, C. M. 2021

View details for DOI 10.1038/s41375-021-01128-1

View details for PubMedID 33483616

The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms. Nature communications Schwartz, J. R., Ma, J., Kamens, J., Westover, T., Walsh, M. P., Brady, S. W., Robert Michael, J., Chen, X., Montefiori, L., Song, G., Wu, G., Wu, H., Branstetter, C., Hiltenbrand, R., Walsh, M. F., Nichols, K. E., Maciaszek, J. L., Liu, Y., Kumar, P., Easton, J., Newman, S., Rubnitz, J. E., Mullighan, C. G., Pounds, S., Zhang, J., Gruber, T., Ma, X., Klco, J. M. 2021; 12 (1): 985


Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n=28, tAML: n=56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.

View details for DOI 10.1038/s41467-021-21255-8

View details for PubMedID 33579957

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML. Cancers Lamba, J. K., Cao, X., Raimondi, S., Downing, J., Ribeiro, R., Gruber, T. A., Rubnitz, J., Pounds, S. 2020; 12 (10)


Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as DNMT3A, IDH1 or IDH2 are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.

View details for DOI 10.3390/cancers12103024

View details for PubMedID 33080932

Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. The Journal of clinical investigation Klossowski, S. n., Miao, H. n., Kempinska, K. n., Wu, T. n., Purohit, T. n., Kim, E. n., Linhares, B. M., Chen, D. n., Jih, G. n., Perkey, E. n., Huang, H. n., He, M. n., Wen, B. n., Wang, Y. n., Yu, K. n., Lee, S. C., Danet-Desnoyers, G. n., Trotman, W. n., Kandarpa, M. n., Cotton, A. n., Abdel-Wahab, O. n., Lei, H. n., Dou, Y. n., Guzman, M. n., Peterson, L. n., Gruber, T. n., Choi, S. n., Sun, D. n., Ren, P. n., Li, L. S., Liu, Y. n., Burrows, F. n., Maillard, I. n., Cierpicki, T. n., Grembecka, J. n. 2020; 130 (2): 98197


The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

View details for DOI 10.1172/JCI129126

View details for PubMedID 31855575

View details for PubMedCentralID PMC6994154

Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Jeha, S. n., Pei, D. n., Choi, J. n., Cheng, C. n., Sandlund, J. T., Coustan-Smith, E. n., Campana, D. n., Inaba, H. n., Rubnitz, J. E., Ribeiro, R. C., Gruber, T. A., Raimondi, S. C., Khan, R. B., Yang, J. J., Mullighan, C. G., Downing, J. R., Evans, W. E., Relling, M. V., Pui, C. H. 2019; 37 (35): 337791


Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control.Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; P = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] v 5.7% [95% CI, 2.8% to 8.6%]; P = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.

View details for DOI 10.1200/JCO.19.01692

View details for PubMedID 31657981

View details for PubMedCentralID PMC7351342

De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. Nature communications Hyrenius-Wittsten, A. n., Pilheden, M. n., Sturesson, H. n., Hansson, J. n., Walsh, M. P., Song, G. n., Kazi, J. U., Liu, J. n., Ramakrishan, R. n., Garcia-Ruiz, C. n., Nance, S. n., Gupta, P. n., Zhang, J. n., Rnnstrand, L. n., Hultquist, A. n., Downing, J. R., Lindkvist-Petersson, K. n., Paulsson, K. n., Jrs, M. n., Gruber, T. A., Ma, J. n., Hagstrm-Andersson, A. K. 2018; 9 (1): 1770


Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the Kras G12D locus, consistent with a strong selective advantage of additional Kras G12D . KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.

View details for DOI 10.1038/s41467-018-04180-1

View details for PubMedID 29720585

View details for PubMedCentralID PMC5932012

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: a retrospective study by the I-BFM Study Group. Blood Noort, S. n., Zimmermann, M. n., Reinhardt, D. n., Cuccuini, W. n., Pigazzi, M. n., Smith, J. n., Ries, R. E., Alonzo, T. A., Hirsch, B. n., Tomizawa, D. n., Locatelli, F. n., Gruber, T. A., Raimondi, S. n., Sonneveld, E. n., Cheuk, D. K., Dworzak, M. n., Stary, J. n., Abrahamsson, J. n., Arad-Cohen, N. n., Czogala, M. n., De Moerloose, B. n., Hasle, H. n., Meshinchi, S. n., van den Heuvel-Eibrink, M. n., Zwaan, C. M. 2018; 132 (15): 158492


To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Mnster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

View details for DOI 10.1182/blood-2018-05-849059

View details for PubMedID 30150206

View details for PubMedCentralID PMC6265640

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature genetics de Rooij, J. D., Branstetter, C. n., Ma, J. n., Li, Y. n., Walsh, M. P., Cheng, J. n., Obulkasim, A. n., Dang, J. n., Easton, J. n., Verboon, L. J., Mulder, H. L., Zimmermann, M. n., Koss, C. n., Gupta, P. n., Edmonson, M. n., Rusch, M. n., Lim, J. Y., Reinhardt, K. n., Pigazzi, M. n., Song, G. n., Yeoh, A. E., Shih, L. Y., Liang, D. C., Halene, S. n., Krause, D. S., Zhang, J. n., Downing, J. R., Locatelli, F. n., Reinhardt, D. n., van den Heuvel-Eibrink, M. M., Zwaan, C. M., Fornerod, M. n., Gruber, T. A. 2017; 49 (3): 45156


Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

View details for DOI 10.1038/ng.3772

View details for PubMedID 28112737

View details for PubMedCentralID PMC5687824

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia Pui, C. H., Pei, D. n., Raimondi, S. C., Coustan-Smith, E. n., Jeha, S. n., Cheng, C. n., Bowman, W. P., Sandlund, J. T., Ribeiro, R. C., Rubnitz, J. E., Inaba, H. n., Gruber, T. A., Leung, W. H., Yang, J. J., Downing, J. R., Evans, W. E., Relling, M. V., Campana, D. n. 2017; 31 (2): 33339


To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was 1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

View details for DOI 10.1038/leu.2016.234

View details for PubMedID 27560110

View details for PubMedCentralID PMC5288281

AMKL chimeric transcription factors are potent inducers of leukemia. Leukemia Dang, J. n., Nance, S. n., Ma, J. n., Cheng, J. n., Walsh, M. P., Vogel, P. n., Easton, J. n., Song, G. n., Rusch, M. n., Gedman, A. L., Koss, C. n., Downing, J. R., Gruber, T. A. 2017; 31 (10): 222834


Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.

View details for DOI 10.1038/leu.2017.51

View details for PubMedID 28174417

View details for PubMedCentralID PMC5791746

The genomic landscape of core-binding factor acute myeloid leukemias. Nature genetics Faber, Z. J., Chen, X. n., Gedman, A. L., Boggs, K. n., Cheng, J. n., Ma, J. n., Radtke, I. n., Chao, J. R., Walsh, M. P., Song, G. n., Andersson, A. K., Dang, J. n., Dong, L. n., Liu, Y. n., Huether, R. n., Cai, Z. n., Mulder, H. n., Wu, G. n., Edmonson, M. n., Rusch, M. n., Qu, C. n., Li, Y. n., Vadodaria, B. n., Wang, J. n., Hedlund, E. n., Cao, X. n., Yergeau, D. n., Nakitandwe, J. n., Pounds, S. B., Shurtleff, S. n., Fulton, R. S., Fulton, L. L., Easton, J. n., Parganas, E. n., Pui, C. H., Rubnitz, J. E., Ding, L. n., Mardis, E. R., Wilson, R. K., Gruber, T. A., Mullighan, C. G., Schlenk, R. F., Paschka, P. n., Dhner, K. n., Dhner, H. n., Bullinger, L. n., Zhang, J. n., Klco, J. M., Downing, J. R. 2016; 48 (12): 155156


Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.

View details for DOI 10.1038/ng.3709

View details for PubMedID 27798625

View details for PubMedCentralID PMC5508996

The genomic landscape of juvenile myelomonocytic leukemia NATURE GENETICS Stieglitz, E., Taylor-Weiner, A. N., Chang, T. Y., Gelston, L. C., Wang, Y., Mazor, T., Esquivel, E., Yu, A., Seepo, S., Olsen, S. R., Rosenberg, M., Archambeault, S. L., Abusin, G., Beckman, K., Brown, P. A., Briones, M., Carcamo, B., Cooper, T., Dahl, G. V., Emanuel, P. D., Fluchel, M. N., Goyal, R. K., Hayashi, R. J., Hitzler, J., Hugge, C., Liu, Y. L., Messinger, Y. H., Mahoney, D. H., Monteleone, P., Nemecek, E. R., Roehrs, P. A., Schore, R. J., Stine, K. C., Takemoto, C. M., Toretsky, J. A., Costello, J. F., Olshen, A. B., Stewart, C., Li, Y., Ma, J., Gerbing, R. B., Alonzo, T. A., Getz, G., Gruber, T. A., Golub, T. R., Stegmaier, K., Loh, M. L. 2015; 47 (11): 1326-?


Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

View details for DOI 10.1038/ng.3400

View details for PubMedID 26457647

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nature genetics Andersson, A. K., Ma, J. n., Wang, J. n., Chen, X. n., Gedman, A. L., Dang, J. n., Nakitandwe, J. n., Holmfeldt, L. n., Parker, M. n., Easton, J. n., Huether, R. n., Kriwacki, R. n., Rusch, M. n., Wu, G. n., Li, Y. n., Mulder, H. n., Raimondi, S. n., Pounds, S. n., Kang, G. n., Shi, L. n., Becksfort, J. n., Gupta, P. n., Payne-Turner, D. n., Vadodaria, B. n., Boggs, K. n., Yergeau, D. n., Manne, J. n., Song, G. n., Edmonson, M. n., Nagahawatte, P. n., Wei, L. n., Cheng, C. n., Pei, D. n., Sutton, R. n., Venn, N. C., Chetcuti, A. n., Rush, A. n., Catchpoole, D. n., Heldrup, J. n., Fioretos, T. n., Lu, C. n., Ding, L. n., Pui, C. H., Shurtleff, S. n., Mullighan, C. G., Mardis, E. R., Wilson, R. K., Gruber, T. A., Zhang, J. n., Downing, J. R. 2015; 47 (4): 33037


Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

View details for DOI 10.1038/ng.3230

View details for PubMedID 25730765

View details for PubMedCentralID PMC4553269

Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. The Lancet. Oncology Pui, C. H., Pei, D. n., Coustan-Smith, E. n., Jeha, S. n., Cheng, C. n., Bowman, W. P., Sandlund, J. T., Ribeiro, R. C., Rubnitz, J. E., Inaba, H. n., Bhojwani, D. n., Gruber, T. A., Leung, W. H., Downing, J. R., Evans, W. E., Relling, M. V., Campana, D. n. 2015; 16 (4): 46574


The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions.Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at, number NCT00137111.Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (692%, 95% CI 496-824, n=36 vs 955%, 917-975, n=244; p<0001 for the provisional low-risk group and 651%, 507-762, n=56 vs 829%, 756-882, n=142; p=001 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<001%) on day 46 were treated for standard-risk ALL and had a 10-year event-free survival of 889% (433-984). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (727%, 425-888 vs 840%, 763-894; p=006) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease.National Institutes of Health and American Lebanese Syrian Associated Charities.

View details for DOI 10.1016/S1470-2045(15)70082-3

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Germline Mutations in Predisposition Genes in Pediatric Cancer. The New England journal of medicine Zhang, J. n., Walsh, M. F., Wu, G. n., Edmonson, M. N., Gruber, T. A., Easton, J. n., Hedges, D. n., Ma, X. n., Zhou, X. n., Yergeau, D. A., Wilkinson, M. R., Vadodaria, B. n., Chen, X. n., McGee, R. B., Hines-Dowell, S. n., Nuccio, R. n., Quinn, E. n., Shurtleff, S. A., Rusch, M. n., Patel, A. n., Becksfort, J. B., Wang, S. n., Weaver, M. S., Ding, L. n., Mardis, E. R., Wilson, R. K., Gajjar, A. n., Ellison, D. W., Pappo, A. S., Pui, C. H., Nichols, K. E., Downing, J. R. 2015; 373 (24): 233646


The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).

View details for DOI 10.1056/NEJMoa1508054

View details for PubMedID 26580448

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Whole-exome sequencing identifies a novel somatic mutation in MMP8 associated with a t(1;22)-acute megakaryoblastic leukemia. Leukemia Kim, Y. n., Schulz, V. P., Satake, N. n., Gruber, T. A., Teixeira, A. M., Halene, S. n., Gallagher, P. G., Krause, D. S. 2014; 28 (4): 94548

View details for DOI 10.1038/leu.2013.314

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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nature communications Huether, R. n., Dong, L. n., Chen, X. n., Wu, G. n., Parker, M. n., Wei, L. n., Ma, J. n., Edmonson, M. N., Hedlund, E. K., Rusch, M. C., Shurtleff, S. A., Mulder, H. L., Boggs, K. n., Vadordaria, B. n., Cheng, J. n., Yergeau, D. n., Song, G. n., Becksfort, J. n., Lemmon, G. n., Weber, C. n., Cai, Z. n., Dang, J. n., Walsh, M. n., Gedman, A. L., Faber, Z. n., Easton, J. n., Gruber, T. n., Kriwacki, R. W., Partridge, J. F., Ding, L. n., Wilson, R. K., Mardis, E. R., Mullighan, C. G., Gilbertson, R. J., Baker, S. J., Zambetti, G. n., Ellison, D. W., Zhang, J. n., Downing, J. R. 2014; 5: 3630


Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.

View details for DOI 10.1038/ncomms4630

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An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer cell Gruber, T. A., Larson Gedman, A. n., Zhang, J. n., Koss, C. S., Marada, S. n., Ta, H. Q., Chen, S. C., Su, X. n., Ogden, S. K., Dang, J. n., Wu, G. n., Gupta, V. n., Andersson, A. K., Pounds, S. n., Shi, L. n., Easton, J. n., Barbato, M. I., Mulder, H. L., Manne, J. n., Wang, J. n., Rusch, M. n., Ranade, S. n., Ganti, R. n., Parker, M. n., Ma, J. n., Radtke, I. n., Ding, L. n., Cazzaniga, G. n., Biondi, A. n., Kornblau, S. M., Ravandi, F. n., Kantarjian, H. n., Nimer, S. D., Dhner, K. n., Dhner, H. n., Ley, T. J., Ballerini, P. n., Shurtleff, S. n., Tomizawa, D. n., Adachi, S. n., Hayashi, Y. n., Tawa, A. n., Shih, L. Y., Liang, D. C., Rubnitz, J. E., Pui, C. H., Mardis, E. R., Wilson, R. K., Downing, J. R. 2012; 22 (5): 68397


To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

View details for DOI 10.1016/j.ccr.2012.10.007

View details for PubMedID 23153540

View details for PubMedCentralID PMC3547667