ZMYM3 (Zinc Finger MYM-Type Containing 3)

P2, N=22, Recruiting, Zulfa Omer | Not yet recruiting --> Recruiting

P2, N=62, Recruiting, Zulfa Omer | Not yet recruiting --> Recruiting | Initiation date: Jun 2025 --> Dec 2025

ZMYM3 S464 emerges as a phospho-regulatory hub that coordinates epigenetic silencing, HR repair, and mitotic fidelity. Its cancer-type-specific upregulation offers a novel biomarker for HR-deficiency stratification and a therapeutic entry point for modulating BRCA1 function or epigenetic drug sensitivity; functional validation in HR-deficient models is now warranted.

This paper presents the results of whole genome sequencing (WGS) of lymphoma cells collected from a 29-year-old woman initially diagnosed with aCLL and successfully treated with fludarabine, cyclophosphamide, and rituximab. Eight years later, due to disease progression, she was treated with ibrutinib...The presence of the other lesions requires further studies and indicates the complex molecular background of aCLL transformation to DLBCL. Therefore, the whole-genome variant assessment is worth considering for introduction into a routine procedure at the time of B-CLL diagnosis, especially when RT is suspected.

By exploring candidates for synthetic lethality, we unexpectedly uncover that KDM1A promotes survival after DAC treatment through interactions with ZMYM3 and CoREST, independent of its demethylase activity or regulation of viral mimicry. These findings emphasize the importance of DNA repair pathways in DAC response and provide potential biomarkers.

Conversely, in sPCL, more diverse variants were detected mainly in BM samples, and VAF was also higher in BM than PB. Considering unique variants detected in PB and the high genetic heterogeneity of the disease, PB should be included in the diagnosis of PCL to determine the exact genetic profile.

Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. JCO 2019, 7(4):269-277

Mutations in ZMYM3 are mainly loss-of-function, associate with NOTCH1 signaling mutations and shorten TFT in CLL patients, suggesting that ZMYM3 mutational status may be a useful marker in the management of early stage CLL patients. Moreover, ZMYM3 mutations reduce histone H4 acetylation and cooperate with NOTCH1 mutations to dysregulate gene-expression, leading to impair DNA damage response and apoptosis evasion.

In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014)...Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis...Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1)... Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

In conclusion, our work shows that ZMYM3 mutations highly associate with NOTCH1 mutations and have an impact in the outcome of CLL patients, especially in early-stage cases. Moreover, we demonstrate that ZMYM3 mutations reduce histone H4 acetylation levels and alter gene expression of CLL cells, resulting in impaired DNA damage repair and promoting apoptosis evasion.

This study highlights scRNA-seq as an efficient method for tracking rare cells potent for causing CLL refractoriness, thus enabling their subsequent detailed characterization. Presented study was funded by the following grants: MH-CZ_AZV_NU20-08-00314, MEYS- CZ_MUNI/A/1224/2022, MH-CZ_RVO_65269705009, NPO_NUVR_LX22NPO5102, TACR_TN02000109. TP53, RNA-seq, B-CLL

Prognostic analysis showed that TP53 mutations might be associated with poor prognosis of intracranial teratomas patients. Our study revealed the genetic characteristics of intracranial teratoma which might be valuable for guiding future targeted therapies.