Additional Genetic Subtypes of Acute Myeloid Leukemia, Including t(6;9), inv(3), t(1;22), Mutated NPM1, Mutated CEBPA



Additional Genetic Subtypes of Acute Myeloid Leukemia, Including t(6;9), inv(3), t(1;22), Mutated NPM1, Mutated CEBPA


David Czuchlewski, MD









While AML with t(6;9)(p23;q34) is often associated with basophilia, some cases (including this one) do not show this feature. Note dysplastic PMN image.






Karyotype reveals a t(6;9)(p23;q34) image, resulting in a DEK-NUP214 fusion. These cases have a relatively poor prognosis and frequently include some degree of basophilia and multilineage dysplasia.


TERMINOLOGY


Definitions



  • Subclassification of acute myeloid leukemia (AML) was historically based on morphologic features



    • The former French-American-British classification followed this approach


  • WHO 2001 classification synthesized morphologic, clinical, immunophenotypic, and genetic information to define subcategories of AML



    • This scheme recognized 4 major types of AML characterized by recurrent genetic abnormalities



      • AML with t(8;21)(q22;q22)


      • AML with inv(16)(p13q22) or t(16;16)(p13;q22)


      • Acute promyelocytic leukemia [AML with t(15;17) (q22;q12) and variants]


      • AML with 11q23 abnormalities


  • WHO 2008 classification, adopting same philosophy as WHO 2001, revised roster of genetically defined AML subtypes



    • Instead of AML with 11q23 abnormalities, specific subset with t(9;11)(p22;q23) was recognized


    • Several additional types of AML defined by recurrent genetic abnormalities were added



      • AML with t(6;9)(p23;q34)


      • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)


      • AML with t(1;22)(p13;q13)


    • In addition, for 1st time, gene mutations (as opposed to recurrent translocations) were deemed to define provisional entities



      • AML with mutated NPM1


      • AML with mutated CEBPA


    • In addition, FLT3 mutations are discussed



      • FLT3 mutations are seen in a number of well-defined subtypes of AML


      • Thus, FLT3 mutations do not define specific subcategory of AML


      • However, FLT3 mutations can significantly affect prognosis, especially in AML with normal cytogenics


ETIOLOGY/PATHOGENESIS


AML with t(6;9)(p23;q34)



  • Produces fusion of DEK and NUP214


AML with inv(3)(q21q26.2) or t(3;3) (q21;q26.2)



  • Produces juxtaposition of RPN1 and EVI1


AML with t(1;22)(p13;q13)



  • Produces fusion of RBM15 and MKL1


AML with Mutated NPM1



  • NPM1 encodes protein nucleophosmin


  • Nucleophosmin appears to play several roles



    • Shuttles other proteins between nucleus and cytoplasm


  • NPM1 mutations involve small insertions in specific region of gene



    • Resulting frameshift causes change in nuclear localization motif in nucleophosmin



      • With this signal altered, protein is aberrantly concentrated in cytoplasm


      • Abnormal cellular localization disturbs functions of nucleophosmin and promotes transformation


AML with Mutated CEBPA



  • CEBPA encodes transcription factor necessary for granulocytic differentiation



    • CEBPA mutations abrogate this function, preventing differentiation of immature granulocytic precursors

Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Additional Genetic Subtypes of Acute Myeloid Leukemia, Including t(6;9), inv(3), t(1;22), Mutated NPM1, Mutated CEBPA
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