CD371 cell surface expression: a unique feature of <i>DUX4</i>-rearranged acute lymphoblastic leukemia

Schinnerl, Dagmar; Mejstříková, Ester; Schumich, Angela; Žaliová, Markéta; Fortschegger, Klaus; Nebral, Karin; Attarbaschi, Andishe; Fišer, Karel; Kauer, Maximilian; Popitsch, Niko; Haslinger, Sabrina; Inthal, Andrea; Buldini, Barbara; Basso, Giuseppe; Bourquin, Jean-Pierre; Gaipa, Giuseppe; Brüggemann, Monika; Feuerstein, Tamar; Maurer‐Granofszky, Margarita; Panzer‐Grümayer, Renate; Trka, Jan; Mann, Georg; Haas, Oskar A.; Hrušák, Ondřej; Dworzak, Michael; Strehl, Sabine

doi:10.3324/haematol.2018.214353

Cited by 43 publications

(39 citation statements)

References 15 publications

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“…This truncated form binds an intragenic region of the ETS-family transcription factor ERG (ETS-related gene) and commonly results in the expression of a C-terminal ERG protein fragment that is a dominant-negative inhibitor of wild-type ERG function. DUX4 -rearranged B-ALL has a unique immunophenotype (CD2 and CD371 positive), and a favorable outcome can be obtained, even with the deletion of IKZF1 , by adjusting the intensity of the chemotherapy based on the MRD [ 31 , 32 ].…”

Section: Low-risk Genetic Subgroupsmentioning

confidence: 99%

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Inaba

Pui

2021

JCM

110

105

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The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

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Section: Low-risk Genetic Subgroupsmentioning

confidence: 99%

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Inaba

Pui

2021

JCM

110

105

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“…Whilst surface expression of CRLF2 lends itself to flow cytometric detection of patients with CRLF2 r [ 61 ], the detection of DUX4 r is reliant upon expression of the cell surface antigen CD371 (CLL-1). This antigen is encoded by CLEC12A , known to be upregulated by DUX4 expression, and was detected on blast cells of DUX4 r cases but shown to be almost absent in all other analysed subtypes in one study [ 62 ]. The few non- DUX4 r samples with CD371 expression were shown to contain alternate subtype-specific lesions detectable by standard cytogenetics.…”

Section: Detecting Dux4 Rmentioning

confidence: 99%

“…The few non- DUX4 r samples with CD371 expression were shown to contain alternate subtype-specific lesions detectable by standard cytogenetics. Aberrant expression of CD2 has also been observed in patients with DUX4 r [ 7 , 55 ] including patients who demonstrate monocytic lineage switch [ 55 , 63 ] and the combination of CD371 and CD2 has recently been suggested as a strong marker for DUX4 r [ 60 , 62 ]. Additional studies are needed to confirm this finding and validate immunophenotyping as an accurate method for detection of DUX4 r patients.…”

Section: Detecting Dux4 Rmentioning

confidence: 99%

DUX Hunting—Clinical Features and Diagnostic Challenges Associated with DUX4-Rearranged Leukaemia

Rehn

O'Connor

White

et al. 2020

Cancers

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DUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links the hypervariable IGH gene to DUX4 a gene located within the D4Z4 macrosatellite repeat on chromosome 4, with a homologous polymorphic repeat on chromosome 10. DUX4r is cryptic to most standard diagnostic techniques, and difficult to identify even with next generation sequencing assays. This review summarises the clinical features and molecular genetics of DUX4r B-ALL and proposes prospective new diagnostic methods.

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“…Our technique clearly revealed an essential function for DUX4 in t(4;14) rearranged ALL (Figure 2i). Expression of the DUX4-IGH translocation was reported to be associated with a defined gene expression signature (28,29); we observed reversal of this signature upon silencing DUX4 in PDX models in vivo ( Figure 2j and Figure S2n). Our technique could thus identify DUX4 as attractive therapeutic target to treat the recently detected subgroup of DUX4-IGH rearranged ALL.…”

Section: Establishing An Inducible Knockdown System In Pdx Acute Lementioning

confidence: 66%

In vivoinducible reverse genetics in patients’ tumors to identify individual therapeutic targets

Carlet

Völse

Vergalli

et al. 2020

Preprint

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High-throughput sequencing describes multiple alterations in each tumor (1), but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient (2). Here, we established a Cre-ER T 2 -loxP based inducible RNAi-mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition was initiated in mice harboring orthotopic tumors. Fluorochrome guided, competitive in vivo trials identified a major tumor-maintaining potency of the MLL-AF4 fusion protein and validated MCL1 as vulnerability in some, but not all patients' tumors. We could prove DUX4 to play an essential role in patients' leukemias carrying the recently described DUX4-IGH translocation. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future. target validation | PDX models of acute leukemia | inducible RNAi | Cre-loxP | MLL-AF4 | MCL1 | DUX4-IGH Correspondence: irmela.jeremias@helmholtz-muenchen.de

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CD371 cell surface expression: a unique feature of DUX4-rearranged acute lymphoblastic leukemia

Cited by 43 publications

References 15 publications

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

DUX Hunting—Clinical Features and Diagnostic Challenges Associated with DUX4-Rearranged Leukaemia

In vivoinducible reverse genetics in patients’ tumors to identify individual therapeutic targets

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