BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia.

Elena Zerkalenkova,Yulia Olshanskaya,Michael Maschan,Aleksandra Borkovskaia,Olga Plekhanova,Aleksey Maschan,Olga Soldatkina,Svetlana Lebedeva,Galina Novichkova,Grigory Tsaur

doi:10.3390/biomedicines9080924

Abstract

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patients’ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subsequent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients.

Highlights

Over the recent years, the novel molecular techniques have substantially changed the face of clinical laboratory diagnostics
KMT2A-rearranged acute leukemia represents one type of such neoplasms that are complex both for diagnostics and treatment. They are commonly found in infant acute lymphoblastic leukemia (ALL)—up to 70–80% [2,3], and with less frequency in ALL or acute myeloid leukemia (AML) in a broader age range of older children or adults [4,5]
KMT2A rearrangements are an important predictor of outcome in acute leukemia, with the prognosis varying from good and intermediate to poor depending on the partner gene and breakpoint location [2,9,10]

Summary

Introduction

The novel molecular techniques have substantially changed the face of clinical laboratory diagnostics. In certain types of hematological malignancies, the cytogenetic studies are still mandatory for classification and risk stratification [1] They uncover most significant chromosomal aberrations in a fast and cost-effective way, selecting peculiar cases for the advanced molecular approach. KMT2A (histone-lysine N-methyltransferase 2A, former MLL)-rearranged acute leukemia represents one type of such neoplasms that are complex both for diagnostics and treatment. They are commonly found in infant acute lymphoblastic leukemia (ALL)—up to 70–80% [2,3], and with less frequency in ALL or acute myeloid leukemia (AML) in a broader age range of older children or adults [4,5]. KMT2A rearrangements are an important predictor of outcome in acute leukemia, with the prognosis varying from good and intermediate to poor depending on the partner gene and breakpoint location [2,9,10]

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