Background: m6A modification, regulated by writers (METTL3, METTL14), erasers (ALKBH5, FTO), and readers (IGF2BPs), is implicated in various cancers, including leukemias. Methods: In our study, we examined a cohort of 227 pediatric B-ALL patients (152 primary and 75 relapsed) and assessed the expression profiles of m6A machinery genes, including both writers and erasers, as well as the IGF2BP RNA-binding proteins, which are known as m6A readers. We also quantified the absolute percentage of m6A (m6A%). The correlation between m6A machinery gene expression and patient prognosis was studied using univariate and multivariate analyses. Results: Our analysis revealed a significant upregulation of m6A writers (METTL3 and METTL14), erasers (FTO), and m6A readers (IGF2BPs 1 and 3) in B-ALL patients, both in the primary and relapsed groups. m6A% levels were markedly higher in B-ALL samples than in controls. Multivariate analysis revealed that the expression of IGF2BP3, METTL3, and FTO genes, independently predicted lower overall survival and event-free survival in primary B-ALL patients. Conclusions: Despite the collective dysregulation of the m6A machinery, the writers and readers appear to have a more dominant phenotype, as evidenced by the significantly elevated m6A% levels. This is the first study to analyze and establish the role of m6A machinery gene expression and its correlation with survival outcomes in a large group of B-ALL patients. These findings could aid in the development of new therapeutics targeting the m6A machinery and help predict relapse in pediatric B-ALL patients.

Although acute myeloid leukemia (AML) with the RUNX1::RUNX1T1 fusion [t(8;21)(q22;q22.1)] defines a distinct cytogenetic subtype, differences in treatment response suggest additional molecular contributors beyond chromosomal abnormalities. Deregulated hematopoietic lineage-specific long non-coding RNAs (lncRNAs) contribute to leukemogenesis and therapy resistance. To investigate their role in t(8;21) AML, we performed whole-transcriptome sequencing of pediatric patients and age-matched healthy controls, identifying significant downregulation of lncRNA HOTAIRM1 , a regulator of myeloid differentiation (adjusted P < 0.05). This was confirmed in a single-cell RNA-sequencing dataset (GSE116256) and the Leukemia MILE dataset (GSE13159, P=0.03). Validation of expression in our study cohort using qPCR specifically demonstrated significant downregulation of the myeloid specific isoform, HOTAIRM1 – HM1V2 (P<0.0001). Analysis of downstream pathways activated by HM1V2 loss identified miR-222 , an oncomiR, as a de-repressed target (P=0.01). Elevated miR-222 expression was observed across AML cell lines (P<0.05), leukemic stem and progenitor cells (GSE117090, P<0.05), AML plasma-derived exosomes (GSE142699, P<0.0001), the current study dataset (P<0.0001), and the TARGET AML dataset (P<0.0001). Restoring HM1V2 expression with epigenetic agents azacytidine and panobinostat induced apoptosis in venetoclax-resistant Kasumi-1 cells (P < 0.01), through suppression of miR-222 (P < 0.01) and downregulation of anti-apoptotic proteins BCL-xL and MCL-1 (P < 0.05), key mediators of the venetoclax resistance mechanism. Machine learning based feature selection and Cox regression analysis showed that high miR-222 expression predicts poor outcome in pediatric t(8;21) AML, validated in both our institutional pediatric AML cohort (P < 0.05) and the multi-institutional TARGET cohort (P < 0.0001). Together, our findings highlight an epigenetic based approach to restore isoform-specific HM1V2 pathway function in venetoclax-resistant AML cells, and identifies miR-222 as a prognostic marker to refine risk stratification within the traditionally favorable-risk t(8;21) AML subgroup. Key Points 1. Loss of myeloid lineage specific isoform of lncRNA HOTAIRM1 - HOTAIRM1 variant 2 , results in de-repression of microRNA miR-222 , and contributes to venetoclax resistance in pediatric AML patients harbouring the t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 fusion. 2. MicroRNA miR-222 shows potential as a single marker predictor that complements current risk stratification by identifying a subset of pediatric t(8;21) AML patients with poor prognosis. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. DST-SERB, Govt. of India All India Institute of Medical Sciences, https://ror.org/02dwcqs71 Council of Scientific and Industrial Research, https://ror.org/021wm7p51 [1]: pending:yes

N-6 Methyl Adenosine (m6A) methylation is primarily found in the 3’-UTRs of mRNAs, near the stop codon, and at consensus sequence RRACH. The methylation reaction is catalyzed by RNA methyltransferases METTL3 and METTL14, known as writers. Readers recognize the modified mRNA, which influences mRNA stability and translation. Insulin-like growth factor-2 binding proteins 1 and 3 (IGF2BP1 and IGF2BP3) are known m6A readers, promoting mRNA stabilization. Erasers like ALKBH5 and FTO remove m6A modifications. Dysregulation of m6A machinery has been implicated in cancer progression. We analyzed the expression patterns of writers, erasers, and readers (WERs) in multiple public datasets, including NCBI-GEO, TCGA, TARGET, and normal tissue expression data from GTEx. Our findings revealed widespread dysregulation of WERs across various cancers. To investigate whether IGF2BP1/3 and METTL3/14 function synergistically in mRNA stabilization, we identified direct mRNA targets using intersection analyses of IGF2BP1/3 eCLIP and METTL3/14 knockout (KO) datasets on Galaxy server. This analysis identified METTL14-dependent targets ( KDM3B, DYNLL1, CNOT1, RPL29 ) and METTL3-dependent targets ( SREBF2, HNF4A, GNA11 ), all bound by IGF2BP1/3. To validate these interactions, we cloned 3’-UTRs of these targets downstream of luciferase reporter and assessed mRNA stability following IGF2BP1/3 and METTL3/14 overexpression. Luciferase activity increased for RPL29, DYNLL1, SREBF2 , and CNOT1 upon co-expression, indicating IGF2BP1/3-mediated mRNA stabilization in an m6A-dependent manner. In contrast, KDM3B, HNF4A, and GNA11 exhibited reduced luciferase activity, suggesting destabilization. Our study provides novel evidence that m6A readers and writers exhibit synergistic and antagonistic interactions in a target-dependent manner, underscoring the complexity of m6A-mediated gene regulation in oncogenesis. ### Competing Interest Statement The authors have declared no competing interest.

Advancements in high-throughput sequencing have significantly expanded our understanding of B-cell Acute Lymphoblastic Leukemia (B-ALL). In particular, whole-transcriptome sequencing (WTS) has facilitated the discovery of the Ph-like ALL subtype. However, clinical integration of WTS remains challenging due to high costs and lack of standardized workflows. Ph-like ALL is marked by genetic heterogeneity, including diverse fusions and mutations, which complicates its diagnosis and limits targeted therapeutic options. This genetic complexity correlates with poor prognosis, emphasizing the need for accessible and effective diagnostic approaches. To develop a cost-effective, qPCR-based diagnostic panel for its detection and classification in clinical settings. A cohort of 394 newly diagnosed B-ALL cases were analyzed using RT-PCR and FISH for initial genetic screening. WTS was employed for comprehensive fusion detection, mutation analysis, and subtype classification. Kaplan-Meier survival analysis was used to evaluate patient outcomes, and a qPCR-based likelihood scoring model was developed based on differential gene expression (DEGs) to identify Ph-like ALL. Whole transcriptome sequencing revealed that 13.1% of the B-ALL cases have Ph-like phenotype, found in different age groups: 9.7% in pediatric patients (n=15), 20.5% in adolescents and young adults (AYA, n=8), and 50% in adults (n=3). Ph-like ALL cases predominantly exhibited fusions involving JAK-STAT pathway genes (n=10), ABL-class genes (n=9), or NTRK1 (n=1), in addition to a novel RUNX1::FGF13 fusion (n=2). Differentially expressed genes were tested for diagnostic potential, with 9 genes (FZH2, PON2, CA6, OLFML2A, BAALC, PRKCZ, ZFPM2, TCFL5 and ENPP2) demonstrating significant ROC (p<0.0001 and sensitivity and specificity >80%) curves in a discovery cohort (n=79). This likelihood model also effectively distinguished Ph-like ALL in a validation cohort (n=150). Additionally, survival analysis revealed significantly worse event-free survival (EFS) and overall survival (OS) in Ph-like ALL patients compared to non-Ph-like patients (EFS: 0% vs. 43.3%, HR 3.40, p=0.006; OS: 0% vs. 45.4%, HR 3.57, p=0.005). This study underscores the genetic diversity of Ph-like ALL. The poor prognosis of Ph-like ALL, marked by significantly reduced EFS and OS, highlights the need for targeted therapeutic approaches. The cost-effective qPCR-based diagnostic panel provides a promising tool for the early detection of Ph-like ALL, offering potential for improved patient outcomes through timely intervention. Anita Chopra, Jay Singh, Mercilena Benjamin, Avanish Pandey, Jayanth Kumar Palanichamy, Sameer Bakhshi, Deepam Pushpam, Akash Kumar Jha, Pranay Tanwar. Unraveling the genetic complexity of Ph-like ALL: development of a cost-effective diagnostic qPCR panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5931.

Background Insulin-like Growth Factor 2 Binding Protein 3 (IGF2BP3) promotes cancer migration and invasion by binding to several coding and non-coding RNAs. Hypoxia stimulates tumor progression by upregulating Hypoxia Inducible Factors and downstream signaling. Quaking ( QKI) gene, which is upregulated in hypoxia and promotes epithelial to mesenchymal transition (EMT), induces circular RNAs. Therefore, the axis between IGF2BP3 , QKI , circular RNAs and their respective host genes under hypoxia was studied. Methods and results Several IGF2BP3-bound circular RNAs were previously identified in HepG2. There were 13 circRNAs originating from 8 host genes bound to IGF2BP3 . We confirmed their binding to IGF2BP3 in U87MG using an RNA Immunoprecipitation assay. MALAT1 , an oncogenic lncRNA was also found to be associated with IGF2BP3 . Three adherent cell lines expressing high levels of IGF2BP3 viz., HeLa, HepG2 and U87MG were cultured under normoxia (20%O 2 ) and hypoxia (<0.2%O 2 ) for 48-168 h. Expression of IGF2BP3 , QKI , EMT markers, IGF2BP3-bound circRNAs and their host mRNAs expression were assessed by quantitative real-time PCR (qRT-PCR) in both normoxia and hypoxia. The hypoxia markers viz., VEGF and CA9 were upregulated in all the cell lines in hypoxia at all time points along with an increase in SNAIL . We found 6 genes, viz., PHC3 , CDYL , ANKRD17 , ARID1A , NEIL3 and FNDC3B with increased expression both at the mRNA and circRNA level indicating their synergistic role in tumor initiation. Overall, we found that circRNA to mRNA expression was observed to be increased for most of the genes and time points of hypoxia in all the cell lines. IGF2BP3 and QKI were also upregulated in hypoxia indicating their role in circRNA biogenesis and stability. Conclusion Our data implies that hypoxia augments circRNA biogenesis which might subsequently play a role in tumor progression.

T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 T-ALL patients to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) Protein-coding genes - BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) Epigenetic modifiers - DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long non-coding RNAs (lncRNAs) - XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 T-ALL patients. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1, demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several novel associations of gene expression patterns with clinicopathological features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide novel prognostic markers.

Oligodendrocytes (OL) are the myelinating cells of the central nervous system that mediate nerve conduction. Loss of oligodendrocytes results in demyelination, triggering neurological deficits. Developing a better understanding of the cell signaling pathways influencing OL development may aid in the development of therapeutic strategies. The primary focus of this study was to investigate and elucidate the cell signaling pathways implicated in the developmental maturation of oligodendrocytes using human fetal neural stem cells (hFNSCs)–derived primary OL and MO3.13 cell line. Successful differentiation into OL was established by examining morphological changes, increased expression of mature OL markers MBP, MOG and decreased expression of pre-OL markers CSPG4 and O4. Analyzing transcriptional datasets (using RNA sequencing) in pre-OL and mature OL derived from hFNSCs revealed the novel and critical involvement of the JAK-STAT cell signaling pathway in terminal OL maturation. The finding was validated in MO3.13 cell line whose differentiation was accompanied by upregulation of IL-6 and the transcription factor STAT3. Increased phosphorylated STAT3 (pY705) levels were demonstrated by western blotting in hFNSCs-derived primary OL as well as terminal maturation in MO3.13 cells, thus validating the involvement of the JAK-STAT pathway in OL maturation. Pharmacological suppression of STAT3 phosphorylation (confirmed by western blotting) was able to prevent the increase of MBP-positive cells as demonstrated by flow cytometry. These novel findings highlight the involvement of the JAK-STAT pathway in OL maturation and raise the possibility of using this as a therapeutic strategy in demyelinating diseases.

T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 patients with T-ALL to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) protein-coding genes-BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) epigenetic modifiers-DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long noncoding RNAs (lncRNAs)-XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 patients with T-ALL. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression was correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1 demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several hitherto unreported associations of gene expression patterns with clinicopathologic features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide prognostic markers.

The etiology of atypical hemolytic uremic syndrome (aHUS) is unknown in 30–40

Introduction Acute myeloid leukemia (AML) is a heterogenous disease categorized into subtypes based on characteristic chromosomal translocations, each having distinct biology. Patients with translocation t(8;21)(q22;q22.1) undergoing conventional chemotherapy show an overall survival of around 50%. Studying subtype-specific biology is crucial to developing targeted therapies and improving patient outcomes. HOTAIRM1, a long non-coding RNA regulates key genes during hematopoiesis, and its expression increases as myeloid cells differentiate. In AML, HOTAIRM1 is deregulated, and we aimed to study the significance of this aberrant expression. Materials and Methods We performed quantitative polymerase chain reaction (qPCR) to study HOTAIRM1 expression in the bone marrow of patients with AML (n=48), and six AML cell lines (Kasumi-1, THP1, HL60, KG1, MOLM13, and MOLM14). Overexpression was achieved by cloning HOTAIRM1 into pcDNA3.1+ vector followed by transfection. Cell cycle and apoptosis assays were performed using flow cytometry. MTT assay was used to calculate inhibitory concentration 50 (IC50) values. Results We found that HOTAIRM1 was significantly downregulated in patients with AML (P=.0005) and in AML cell lines (P<.01), especially in the t(8;21) positive subgroup. Overexpressing HOTAIRM1 led to cell cycle arrest (P<.01) and increased apoptosis (P<.01) in t(8;21) positive Kasumi-1 cells, indicating specific regulation of HOTAIRM1 in this subtype. We identified over-expressed microRNA miR-222 as a potential regulator of HOTAIRM1 expression in Kasumi-1. High miR-222 expression was associated with significantly lower overall survival (P=.02). Inhibiting miR-222 in Kasumi-1 mirrored the effect of HOTAIRM1 overexpression, resulting in cell cycle arrest (P<.001) mediated by p27 protein upregulation and increased apoptosis (P<.001) via BCL2, BCLXL, and MCL1 proteins. Inhibiting miR-222 however, did not increase HOTAIRM1 expression. Interestingly, HOTAIRM1 overexpression in Kasumi-1 led to reduced miR-222 (P<.05) indicating HOTAIRM1’s role in regulating miR-222, not vice versa. Treating Kasumi-1 cells with the hypomethylating drug azacytidine increased HOTAIRM1 expression (P<.0001) suggesting that aberrant promoter hypermethylation contributes to low HOTAIRM1 expression in the t(8;21) positive subtype. Conclusion Our data indicate that rescuing HOTAIRM1 expression in Kasumi-1 cells with drugs such as azacytidine, leads to inhibition of leukemic phenotypes driven by oncogenic miR-222. This suggests that targeting the non-coding RNA HOTAIRM1-miR-222 pathway could be a novel therapeutic approach in t(8;21) AML.

Lung cancer is one of the common cancers globally with high mortality and poor prognosis. Most cases of lung cancer are diagnosed at an advanced stage due to limited diagnostic resources. Screening modalities, such as sputum cytology and annual chest radiographs, have not proved sensitive enough to impact mortality. In recent years, annual low-dose computed tomography has emerged as a potential screening tool for early lung cancer detection, but it may not be a feasible option for developing countries. In this context, exhaled breath condensate (EBC) analysis has been evaluated recently as a noninvasive tool for lung cancer diagnosis. The breath biomarkers also have the advantage of differentiating various types and stages of lung cancer. Recent studies have focused more on microRNAs (miRNAs) as they play a key role in tumourigenesis by regulating the cell cycle, metastasis and angiogenesis. In this review, we have consolidated the current published literature suggesting the utility of miRNAs in EBC for the detection of lung cancer.

Hypoxic insult to the fetal brain causes loss of vulnerable premyelinating oligodendrocytes and arrested oligodendrocyte differentiation. Astrocytes influence oligodendrocyte differentiation and the astrocytic response to hypoxia could affect oligodendrocyte maturation under hypoxia. To identify pathways by which astrocytes influence oligodendroglial maturation in hypoxic injury, human fetal neural stem cell-derived astrocytes were exposed to 0.2 % oxygen for 48 hours. Transcriptomic analysis revealed the upregulation of the cholesterolbiosynthesis pathway in hypoxia-exposed astrocytes. Hypoxia-exposed primary astrocytes and astrocytic cell line (SVG) showed increased expression of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), squalene epoxidase (SQLE), apolipoprotein E (apoE) and ATP-binding cassette transporter 1 (ABCA1) on qPCR and Western blot. Hypoxic SVG also showed increased cholesterol content in cells and culture supernatants and increased cell surface expression of ABCA1. Interestingly hypoxia-exposed premyelinating oligodendrocytes (Mo3.13) showed reduced cholesterol along with decreased expression of HMGCR and SQLE on qPCR and Western blot. Exogenous cholesterol increased the differentiation of Mo3.13 as measured by increased expression of myelin basic protein (MBP) on flow cytometry. Hypoxia exposure resulted in increased cholesterol transport from astrocytes to oligodendrocytes in cocultures with BODIPY-cholesterol labelled SVG and membrane-labelled Mo3.13. As exogenous cholesterol enhanced oligodendrocyte differentiation, our findings indicate that increased cholesterol synthesis by astrocytes and transport to oligodendrocytes could supplement oligodendroglial maturation in conditions of hypoxic brain injury in neonates.

Hematopoiesis is a tightly regulated process that produces all adult blood cells and immune cells from multipotent hematopoietic stem cells (HSCs). HSCs usually remain quiescent, and in the presence of external stimuli like infection or inflammation, they undergo division and differentiation as a compensatory mechanism. Normal hematopoiesis is impacted by systemic inflammation, which causes HSCs to transition from quiescence to emergency myelopoiesis. At the molecular level, inflammatory cytokine signaling molecules such as tumor necrosis factor (TNF), interferons, interleukins, and toll-like receptors can all cause HSCs to multiply directly. These cytokines actively encourage HSC activation, proliferation, and differentiation during inflammation, which results in the generation and activation of immune cells required to combat acute injury. The bone marrow niche provides numerous soluble and stromal cell signals, which are essential for maintaining normal homeostasis and output of the bone marrow cells. Inflammatory signals also impact this bone marrow microenvironment called the HSC niche to regulate the inflammatory-induced hematopoiesis. Continuous pro-inflammatory cytokine and chemokine activation can have detrimental effects on the hematopoietic system, which can lead to cancer development, HSC depletion, and bone marrow failure. Reactive oxygen species (ROS), which damage DNA and ultimately lead to the transformation of HSCs into cancerous cells, are produced due to chronic inflammation. The biological elements of the HSC niche produce pro-inflammatory cytokines that cause clonal growth and the development of leukemic stem cells (LSCs) in hematological malignancies. The processes underlying how inflammation affects hematological malignancies are still not fully understood. In this review, we emphasize the effects of inflammation on normal hematopoiesis, the part it plays in the development and progression of hematological malignancies, and potential therapeutic applications for targeting these pathways for therapy in hematological malignancies.

INTRODUCTION:Acute myeloid leukemia with normal cytogenetics (CN-AML) represents a heterogeneous group having diverse genetic mutations. Understanding the significance of each of these mutations is necessary. In this study, we evaluated the prognostic role of MN1 expression in adult CN-AML patients. METHOD:One hundred and sixty-three de-novo adult AML patients were evaluated for MN1 expression by real-time PCR. MN1 expression was correlated with the clinical characteristics of the patients and their outcomes. RESULTS:Higher MN1 expression was associated with NPM1 wild-type (p<0.0001), CD34 positivity (p=0.006), and lower clinical remission rate (p=0.027). FLT3-ITD and CEBPA mutations had no association with MN1 expression. On survival analysis, a high MN1 expression was associated with poor event-free survival (Hazard Ratio 2.47, 95% Confidence Interval: 1.42-4.3; p<0.0001) and overall survival (Hazard Ratio 4.18, 95% Confidence Interval: 2.17-8.08; p<0.0001). On multivariate analysis, the MN1 copy number emerged as an independent predictor of EFS (p<0.0001) and OS (p<0.0001). CONCLUSION:MN1 expression is an independent predictor of outcome in CN-AML.

Loss of function in the tumor suppressor gene TP53 is the most common alteration seen in human cancer. In mice, P53 deletion in all cells leads predominantly to the development of T-cell lymphomas, followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of P53 in the hematopoietic system, we generated and analyzed two different mouse models deficient for P53. A pan-hematopoietic P53 deletion mouse was created using Vav1-Cre based deletion; and a B-cell-specific deletion mouse was created using a CD19-Cre based deletion. The Vav1-P53CKO mice predominantly developed T-cell malignancies in younger mice, and myeloid malignancies in older mice. In T-cell malignancies, there was accelerated thymic cell maturation with overexpression of Notch1 and its downstream effectors. CD19-P53CKO mice developed marginal zone expansion in the spleen, followed by marginal zone lymphoma, some of which progressed to diffuse large B-cell lymphomas. Interestingly, marginal zone and diffuse large B-cell lymphomas had a unique gene expression signature characterized by activation of the PI3K pathway, compared with wild type marginal zone or follicular cells of the spleen. This study demonstrates lineage specific P53 deletion leading to distinct phenotypes secondary to unique gene expression programs set in motion.