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Overview of Molecular Markers in AML

Overview of Molecular Markers in AML. Nilam Virani Molecular Diagnostics July 28, 2011. AML Classification. FAB Classification. 2008 WHO Classification. Cytogenetic Abnormalities. Swerdlow et al. 2008. Molecular Abnormalities. KIT Mutations in CBF AMLs.

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Overview of Molecular Markers in AML

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  1. Overview of Molecular Markers in AML Nilam Virani Molecular Diagnostics July 28, 2011

  2. AML Classification FAB Classification 2008 WHO Classification

  3. Cytogenetic Abnormalities Swerdlow et al. 2008

  4. Molecular Abnormalities

  5. KIT Mutations in CBF AMLs • 10-20% of the CBF AMLs have KIT mutations • While the cytogenetic abnormalities that define CBF AMLs normally confer a good prognosis, those with KIT mutations do poorly inv(16) t(8;21) Paschka et al., J Clin Oncol, 2006

  6. Prognostic Significance of Molecular Markers

  7. FLT3 Mutations • Member of the the class III receptor tyrosine kinase family • Important role in proliferation, survival, and differentiation of hematopoietic progenitor cells • Mutations result in constitutive activation of FLT3 • 30% of CN-AML have mutations in FLT3 • ITDs result from duplication and tandem insertion of small, variably sized (3-400 nt) gene fragments • TKDs are point mutations, small insertions, or deletions that occur in activation loop in the carboxyterminal lobe, mainly at codons 835 and 836 • Identification of the ITD mutation involves a PCR-based assay that can detect the larger PCR products indicative of duplication

  8. FLT3 Mutations • Prognosis of CN-AML with FLT3-ITD is significantly inferior compared with FLT3-ITD negative CN-AML • Prognostic relevance of FLT3-TKD is not as well-established, but also appears to be unfavorable • Therapeutically, there is accumulating evidence that allogeneic HSCT is an attractive option, given the poor outcome with standard chemotherapy • Randomized phase III trials evaluating FLT3 inhibitors are underway

  9. NPM1 Mutations • Multifunctional phosphoprotein that travels between nuclear compartments and the cytoplasm • Normally, predominantly located in the nucleolus • Implicated in ribosome assembly and regulation of ARF and p53 tumor suppressor function • Mutations were first discovered by IHC because of cytoplasmic mislocation of the mutated NPM1 protein • 50-60% of CN-AML show NPM1 mutations • Detection of the mutations involves a PCR-based assay • >40 mutations have been identified within exon 12 of the gene, but virtually all lead to a net insertion of 4 nt

  10. NPM1 Mutations • Prognostic implications due to NPM1 mutations must be made in the context of FLT3 mutations • Only NPM1mut/FLT3-ITDneg are associated with achievement of complete remission and favorable outcome • Potential marker for disease monitoring • Standard induction chemo followed by 3-4 cycles of high-dose cytarabine is the recommended therapy • Patients may not be considered candidates for allogeneic HSCT in first complete remission • May become important marker for disease monitoring

  11. CEBPA Mutations • Transcription factor whose function is crucial for the development and differentiation of granulocytes from hematopoietic precursors • Mutations lead to a loss of function, and thought to promote leukemogenesis by blocking granulocyte differentiation • 15% of CN-AML have CEBPA mutations • Variety of mutations occur throughout the coding region, but fall into two major types: • N-terminal frameshift → truncation of protein • C-terminal in-frame → impaired dimerization and DNA binding • Identification of mutations requires DNA sequencing • Majority of mutations are biallelic, compound heterozygous mutations

  12. CEBPA Mutations • Only double mutations are associated with a favorable outcome • A series of cases with silencing of CEBPA have been identified, and associated with a distinctly poor prognosis • Standard induction chemo followed by 3-4 cycles of high-dose cytarabine is the recommended therapy • Patients may not be considered candidates for allogeneic HSCT in first complete remission

  13. More molecular markers under investigation Unfavorable recurrent genetic abnormalities Unfavorable overexpression of single genes BAALC ERG EVI1 MN1 • IDH1, IDH2 • WT1 • MLL-PTD • NRAS • KRAS • TP53 • TET2 • ASXL2 • RUNX1 • DNMT3A

  14. References Betz B, Hess JL: Acute Myeloid Leukemia Diagnosis in the 21st Century. Arch Pathol Lab Med 134:1427-33, 2010. Gorello P, et al: Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosphomin (NPM1) gene mutations. Leukemia 20(6):1103-1108, 2006. Gregory TK, et al: Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. Journal of Hematology and Oncology 2:23, 2009. Marcucci G, Haferlach T, Dohner H: Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications. Journal of Clinical Oncology 29:475-86, 2011. Schlenk RF, Dohner K, Krauter J, et al: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: WHO Press; 2008.

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