Acute myeloid leukemia with t(10;11)(p11‐12;q23.3): Results of Russian Pediatric AML registration study

Abstract

Introduction Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A‐MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11‐12—NEBL and ABI1, so they could not be distinguished by conventional cytogenetics. Methods In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11‐12. G‐banding, FISH, reverse transcription PCR, and long‐distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients. Results We demonstrate that 25 patients harbor the KMT2A‐MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A‐NEBL; 1× KMT2A‐ABI1). Conclusions Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11‐12;q23.3).

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

“…KMT2A‐MLLT10 a fascinating MLLT10 r lesion for two reasons. First, unlike PICALM‐MLLT10 and DDX3X‐MLLT10 , KMT2A‐MLLT10 presents as a complex chromosomal rearrangement due to the opposing transcriptional orientations of KMT2A and MLLT10 , typically involving an in‐frame or out‐of‐frame three‐way rearrangement 8,45 . It is also distinct from other MLLT10 r because it involves the KMT2A gene.…”

“…It is also distinct from other MLLT10 r because it involves the KMT2A gene. KMT2A‐MLLT10 therefore overlaps with two known genomic subtypes of acute leukemia, and is subsequently often categorized as both a KMT2A r 8,45 and MLLT10 r 10 . It is likely that KMT2A is the dominant leukemic driver in this fusion, based on the observation that no other MLLT10 r occurs in B‐ALL, whereas KMT2A r B‐ALL occurs with over 70 different fusion partners 44 …”

“…D, KMT2A-MLLT10 conserves the N-terminal domains of KMT2A responsible for protein interactions and non-specific DNA binding, including the menin-binding domain, AT hook, subnuclear localization (SNL) domains and CxxC region, but the repression domain (RD) involved in mediation of transcriptional repression is typically truncated 44. KMT2A-MLLT10 breakpoints are widely variable, typically located within the 8.3 kb breakpoint cluster region of KMT2A spanning introns 9 to 14,44 and have been identified across introns 1 to 18 in MLLT10, most frequently introns 8 and 9 45. [Color figure can be viewed at wileyonlinelibrary.com] suggesting activation of common pathways in both subtypes.…”

Quantification of NG2‐positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia

“…Total DNA and RNA were simultaneously extracted from the bone marrow samples using the InnuPrep DNA/RNA Mini Kit (Analytik Jena AG, Jena, Germany). Routine reverse transcription‐polymerase chain reaction (RT‐PCR) for the detection of the 8 most common KMT2A rearrangements was performed on cDNA using the following multiplex system: forward KMT2A primers with TaqMan probes 29 and reverse EPS15 , 30 AFF1 , MLLT3 , MLLT1 , 29 AFDN , 31 MLLT10 , 32 MLLT6 33 and ELL 34 primers. Samples with KMT2A ‐r that were negative for these translocations were further analyzed either on the DNA level by long‐distance inverse‐polymerase chain reaction (LDI‐PCR) 35 and KMT2A ‐targeted custom NGS panel 36 or on the RNA level by anchored multiplex PCR (ArcherDX, Boulder, CO).…”

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

“…Total DNA and RNA were simultaneously extracted from the whole bone marrow samples using the InnuPrep DNA/RNA Mini Kit (Analytik Jena AG, Jena, Germany). Eight most common KMT2A fusions were excluded by the reverse transcription-polymerase chain reaction (RT-PCR) with forward KMT2A primers and TaqMan probes [20] with reverse EPS15 [21], AFF1, MLLT3, MLLT1 [20], AFDN [22], MLLT10 [23], MLLT6 [24], and ELL [25] primers. To detect unknown KMT2A fusion transcripts, NGS with anchored multiplex PCR target enrichment by the FusionPlex Myeloid panel (ArcherDX, Boulder, CO, USA) was used.…”