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Last Updated: 07/08/15

Molecular Signatures for Outcome Prediction and Therapeutic Targeting in ALL

Cheryl L. Willman, MD
University of New Mexico, Albuquerque, NM

Dr. Willman’s program will expand on the work accomplished under SPECS I, in which microarray-based gene-expression signatures that are highly predictive of relapse-free survival in high-risk acute lymphoblastic leukemia (ALL) were developed. Newly-discovered mutations and potential therapeutic targets measured on multiple genomic platforms will now be incorporated into the design and testing of new molecular classification algorithms. These will be used in concert with the expression classifiers to further refine diagnosis and treatment determination. Despite significant recent improvements, overall outcomes in pediatric ALL remain poor, and the development of accurate predictive molecular risk classification schemes could have significant clinical impact applicable not only to childhood, but to adolescent-young adult (AYA) and adult ALL as well.

Collaborators:

  • The project team includes investigators from the University of New Mexico, Nationwide Children’s Medical Center/Ohio State University, University of California San Francisco, Fred Hutchinson Cancer Research Center (FHCRC), and two NCI Cooperative Groups, the Childrens’ Oncology Group (COG) and SWOG.
  • Data management and statistical support is provided by the UNM Center for Advanced Research Computing as well as by each of the collaborators and the Cooperative Groups.
  • Specimens will be obtained primarily from three sources: the SWOG ALL bank at FHCRC, the AYA ALL Intergroup study C10403, and the COG Tissue Repository at Nationwide Children’s Medical Center.

Projects:

  • Refine microarray-based gene expression classifiers to the best and final set of predictive genes and translate the quantitative measurement of these multi-analyte signatures to a robust clinical diagnostic platform.
  • Confirm and validate the multi-analyte gene expression classifier in a new prospective cohort of 500 high-risk ALL cases already accrued to COG trials and assess its predictive power relative to newly discovered molecular abnormalities (IKZF1, JAK) and other known risk factors (such as assays to determine the functional status of signaling pathways in patients with kinase mutations to predict who will respond to inhibitor therapies).
  • Prospectively test the predictive power of the new molecular signatures and risk classification algorithms in the next generation of COG high-risk ALL clinical trials that will accrue 3000 newly diagnosed children over 5 years.

Publications:

Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.

Authors: Ma, X., Edmonson, M., Yergeau, D., et al.

Source: Nat Commun. 2015 Mar 19;6:6604

Abstract: There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

Authors: Perez-Andreu, V., K. G. Roberts, Xu, H., et al.

Source: Blood. 2015 Jan 22;125(4):680-6

Abstract: Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P </= 5 x 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 x 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 x 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 x 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

Authors: Roberts, K. G., Y. Li, Payne-Turner, D., et al.

Source: N Engl J Med. 2014 Sep 11;371(11):1005-15

Abstract: BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.

Authors: Shojaee, S., R. Caeser, Buchner, M., et al.

Source: Cancer Cell. 2015 Jun 9. pii: S1535-6108(15)00184-1

Abstract: Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance.

Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia.

Authors: Suryani, S., Bracken, L.S., Harvey, R.C., et al.

Source: Mol Cancer Ther. 2015 Feb;14(2):364-74

Abstract: Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL.