ZNF384 rearrangement is the most frequent genetic lesion in adult PH-negative and Ph-like-negative B-other acute lymphoblastic leukemia. Biological and clinical findings

Chiaretti, Sabina; Taherinasab, Akram; Starza, Irene Della; Canichella, Martina; Ansuinelli, Michela; Propris, Maria Stefania De; Messina, Monica; Spinelli, Orietta; Santoro, Alessandra; Novi, Lucia Anna De; Cardinali, Deborah; Schipani, Mattia; Arena, Valentina; Bassan, Renato; Guarini, Anna; Foà, Robin

doi:10.1080/10428194.2022.2148217

Cited by 3 publications

(2 citation statements)

References 14 publications

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“… 9 , 13 , 14 , 16 , 17 , 18 , 20 , 21 Three independent studies have reported a favorable outcome for adult patients with ZNF384 fusions, so we included these cases in the GR-GEN group. 9 , 22 , 23 The impact of additional putative HR-GEN (eg, IKZF1 deletion, IKZF1plus, and ABL-class fusions) in relation to EWALL-PI should be evaluated prospectively.…”

Section: Discussionmentioning

confidence: 99%

A robust and validated integrated prognostic index for defining risk groups in adult acute lymphoblastic leukemia: an EWALL collaborative study

Enshaei,

Joy,

Butler

et al. 2024

Blood Advances

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Risk stratification is crucial to the successful treatment of ALL. Although numerous risk factors have been identified, an optimal prognostic model for integrating variables has not been developed. We used individual patient data from four contemporary academic national clinical trials: UKALL14, NILG-ALL10/07, GIMEMA-LAL1913, PETHEMA-ALL-HR2011 to generate and validate the EWALL prognostic index (EWALL-PI) which is based on white blood cell count, genetics, and end of induction minimal residual disease. Individual patient risk scores were calculated for 778 patients in complete remission aged 15-67 years old using the validated UKALL-PI formula; applying minor modifications to reflect differences between paediatric and adult ALL. Per-trial analysis revealed that EWALL-PI correlated with relapse and death. Regression analysis revealed that each unit increase in EWALL-PI increased the risk of relapse or death by ~30% with no evidence of heterogeneity across trials or patient subgroups. EWALL-PI-defined risk models outperformed the stratification algorithms used by each trial. Threshold analysis revealed an EWALL-PI threshold that divided B and T-cell patients into standard (EWALL-PI <2·50) and high (EWALL-PI ≥2·50) risk groups. Per-trial analysis showed that high-risk patients had a significantly increased relapse rate and inferior survival compared with standard-risk patients (subdistribution hazard ratio ranged from 1.85 to 3.28 for relapse and hazard ratio 1.73 to 3.03 for death). Subgroup analysis confirmed the robustness of these risk groups by sex, age, white cell count and lineage. In conclusion, we validated an integrated risk model across four independent adult ALL clinical trials demonstrating its utility defining clinically relevant risk groups.

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Section: Discussionmentioning

confidence: 99%

A robust and validated integrated prognostic index for defining risk groups in adult acute lymphoblastic leukemia: an EWALL collaborative study

Enshaei,

Joy,

Butler

et al. 2024

Blood Advances

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“…The frequencies are 23 and 3%, respectively 8,9 . They are also frequent in China and Italy, comprising 19% and 9% of B‐ALL without major genetic abnormalities such as BCR::ABL1, TCF3::PBX1, ETV6::RUNX1 , or KMT2A rearrangement, 10,11 respectively, suggesting that they are tend to be more frequent in Asian patients. We and others demonstrated the development of leukemia by introducing a Z‐fusion gene into mouse hematopoietic cells, strongly indicating its leukemogenicity 12–14 .…”

Section: Introductionmentioning

confidence: 99%

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

Yamada,

Okada,

Odaira

et al. 2024

Cancer Medicine

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BackgroundZNF384‐fusion (Z‐fusion) genes were recently identified in B‐cell acute lymphoblastic leukemia (B‐ALL) and are frequent in Japanese adult patients. The frequency is about 20% in those with Philadelphia chromosome‐negative B‐ALL. ZNF384 is a transcription factor and Z‐fusion proteins have increased transcriptional activity; however, the detailed mechanisms of leukemogenesis of Z‐fusion proteins have yet to be clarified.MethodsWe established three transfectants of cell lines expressing different types of Z‐fusion proteins, and analyzed their gene expression profile (GEP) by RNA‐seq. We also analyzed the GEP of clinical ALL samples using our previous RNA‐seq data of 323 Japanese ALL patients. We selected upregulated genes in both Z‐fusion gene‐expressing transfectants and Z‐fusion gene‐positive ALL samples, and investigated the binding of Z‐fusion proteins to regulatory regions of the candidate genes by ChIP‐qPCR.ResultsWe selected six commonly upregulated genes. After the investigation by ChIP‐qPCR, we finally identified CREB5 and RGS1 as direct and common target genes. RGS1 is an inhibitor of CXCL12‐CXCR4 signaling that is required for the homing of hematopoietic progenitor cells to the bone marrow microenvironment and development of B cells. Consistent with this, Z‐fusion gene transfectants showed impaired migration toward CXCL12.ConclusionsWe identified CREB5 and RGS1 as direct and common transcriptional targets of Z‐fusion proteins. The present results provide novel insight into the aberrant transcriptional regulation by Z‐fusion proteins.

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FISH combined with RT-PCR facilitates classification of Chinese adult patients with B-other ALL through improved identification of ZNF384 rearrangement

Li,

Xing,

Zhang

et al. 2024

Leukemia & Lymphoma

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ZNF384 rearrangement is the most frequent genetic lesion in adult PH-negative and Ph-like-negative B-other acute lymphoblastic leukemia. Biological and clinical findings

Cited by 3 publications

References 14 publications

A robust and validated integrated prognostic index for defining risk groups in adult acute lymphoblastic leukemia: an EWALL collaborative study

A robust and validated integrated prognostic index for defining risk groups in adult acute lymphoblastic leukemia: an EWALL collaborative study

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

FISH combined with RT-PCR facilitates classification of Chinese adult patients with B-other ALL through improved identification of ZNF384 rearrangement

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