Gene expression profiling of pediatric acute myelogenous leukemia

Abstract

Contemporary treatment of pediatric acute myeloid leukemia (AML) requires the assignment of patients to specific risk groups. To explore whether expression profiling of leukemic blasts could accurately distinguish between the known risk groups of AML, we analyzed 130 pediatric and 20 adult AML diagnostic bone marrow or peripheral blood samples using the Affymetrix U133A microarray. Class discriminating genes were identified for each of the major prognostic subtypes of pediatric AML, including t(15;17) [ PML-RAR␣], t(8;21)[AML1-ETO], inv 16 [CBF␤-MYH11], MLL chimeric fusion genes, and cases classified as FAB-M7. When subsets of these genes were used in supervised learning algorithms, an overall classification accuracy of more than 93% was achieved. Moreover, we were able to use the expression signatures generated from the pediatric samples to accurately classify adult de novo AMLs with the same genetic lesions. The class discriminating genes also provided novel insights into the molecular pathobiology of these leukemias. Finally, using a combined pediatric data set of 130 AMLs and 137 acute lymphoblastic leukemias, we identified an expression signature for cases with MLL chimeric fusion genes irrespective of lineage. Surprisingly, AMLs containing partial tandem duplications of MLL failed to cluster with MLL chimeric fusion gene cases, suggesting a significant difference in their underlying mechanism of transformation. IntroductionAcute myeloid leukemia (AML) is a relatively rare malignancy in the pediatric population, comprising only 15% to 20% of the acute leukemias diagnosed in this age group. 1 Nevertheless, it remains a challenging disease with an inferior treatment outcome compared with pediatric acute lymphoblastic leukemia (ALL). Despite the introduction of new drugs, the aggressive use of allogeneic and autologous bone marrow transplantation, and improvements in supportive care, overall cure rates of AML in most contemporary treatment protocols remain below 60%. [2][3][4][5] Further improvements in cure rates are likely to come from a better understanding of both the molecular abnormalities responsible for the formation and growth of the leukemic cells, and the mechanisms underlying drug resistance.Increasingly, contemporary treatment protocols are incorporating methods for both accurate diagnosis and subsequent risk stratification. To achieve this requires not only distinguishing myeloblasts from lymphoblasts, but also assessing the extent of lineage commitment and differentiation, as well as the presence of specific molecular lesions or chromosomal abnormalities. Efforts over the last several decades have revealed AML to be a heterogeneous disease, with marked differences in cure rates between various genetic subtypes. [6][7][8][9] Acute promyelocytic leukemia was the first clear example of a clinically distinct AML subtype, being characterized by FAB-M3 morphology and expression of the t(15;17)-encoded promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR␣) fusion protein. [10][11][12][13][14] ...

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…Hence, the incidence of MLL-rearranged AML decreases with age. This is in contrast to the frequency of MLL-PTD, which is equally low in pediatric AML, ranging from 1 to 10% depending on the screening method, 13,[37][38][39] as well as in adult AML, in the range of 5-10%. 37,[40][41][42][43][44][45][46][47] The different translocation partners of the rearranged MLL gene So far, more than 60 different fusion partners of MLL have been identified.…”

“…61 In gene expression profiling (GEP) studies, MLL-rearranged cases clustered together as one group in AML as well as in ALL. 13,[62][63][64] However, our laboratory showed that within MLL-rearranged infant ALL each type of MLL translocation is associated with a translocation-specific gene expression signature. 65 We identified a specific gene expression signature for the total group of MLL-rearranged AML cases, 12 but were also able to identify a specific signature for t(9;11)(p22;q23).…”

“…The MLL fusion most likely disrupts the MLL complex, leading to inappropriate expression of specific HOX genes, that is, HOXA4, HOXA5, HOXA9 and HOXA10, in pediatric MLL-rearranged AML. 13 In addition, the HOX cofactor MEIS1 is upregulated in MLL-rearranged AML. 13 In general, HOX gene expression has a key role in the regulation of hematopoietic development.…”

“…13 In addition, the HOX cofactor MEIS1 is upregulated in MLL-rearranged AML. 13 In general, HOX gene expression has a key role in the regulation of hematopoietic development. Overexpression of HOXA9 results in increased numbers of self-renewing hematopoietic stem cells.…”

“…11 In pediatric AML, MLL-rearranged AML presents with a distinct, unique, expression profile as compared with MLL-PTD. 12,13 Therefore, MLL-rearranged AML and MLL-PTD are considered two different entities.…”