Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes

Koichi Takahashi,Chang Jiun Wu,Abdallah Abou Zhar,Rebecca Thornton,Elias Jabbour,Pei Zhao,Akifumi Takaori‐Kondo ,Nitin Jain,Guillermo Garcia‐Manero ,Peter Hu,Jorge Cortes ,Courtney D Dinardo,Erika J Thompson ,Marisela Mendoza,Yuanqing Yan,Michael Andreeff,Kiyomi Morita,Samantha Tippen,Curtis Gumbs,Marina Konopleva,Steven M Kornblau ,Hagop M Kantarjian ,Feng Wang,Carlos E Bueso‐Ramos ,Latasha Little,Marcus Coyle,Keyur P Patel ,Farhad Ravandi,Jianhua Zhang,P Andrew Futreal

doi:10.1038/s41467-018-04924-z

Abstract

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.

Highlights

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers
Assessment of clonality based on the estimated cancer cell fraction (CCF) of the mutations revealed that RUNX1, DNMT3A, IDH2, SRSF2, KRAS, and TET2 mutations were frequently clonal, whereas mutations in FLT3, ETV6, TP53, and other rare genes were often subclonal or minimally subclonal (Fig. 1c, d)
There was no significant difference in the characteristics between these 31 patients and 24 patients who were not eligible for the study because of prior therapy or nonavailability of the samples (Supplementary Table 3)

Summary

Introduction

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. Acute leukemia generally presents with either a myeloid or lymphoid lineage, rare cases present with blasts that show immunophenotypes of both myeloid and lymphoid lineages (biphenotypic) or with multiple blasts each having different lineage of immunophenotypes (bi-lineal) Such types of acute leukemia are classified as mixed phenotype acute leukemia (MPAL), which accounts for 1–3% of acute leukemias in adults[1]. We compare the frequency of cancer gene mutations in MPAL to those of other lineage-committed acute leukemias (AML, B-ALL, and T-ALL) that were sequenced using the same platform (Fig. 1e).

Methods

Results

Conclusion