Biology subjects

Ghoda, L.

Publications and source records attributed to Ghoda, L..

4 recordsLinked to original sources

bioRxiv2025

Longitudinal single cell RNA-sequencing reveals evolution of micro- and macro-states in chronic myeloid leukemia

Single cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cancer, yet identifying meaningful disease states from single cell data remains challenging. Here, we systematically explore the chronic myeloid leukemia (CML) specific information content encoded in single cell versus bulk transcriptomics to resolve this paradox and clarify how discrete disease-defining states emerge from inherently noisy single cell data. We demonstrate that, while CML single cell transcriptomes exist along continuous transcriptional microstates, clinically relevant leukemia phenotypes clearly manifest only at the pseudobulk (macrostate) level. By leveraging state-transition theory, we reveal how robust disease phenotype state-transitions are governed by cell type specific contributions. Our results establish a theoretical framework explaining why discrete disease phenotypes remain hidden at the single cell scale but emerge clearly at the aggregated macrostate level, enabling previously inaccessible biological insights into leukemia evolution. By resolving how single-cell variation aggregates into macroscopic disease states, our framework provides new insight into CML progression and offers a broadly applicable strategy for exploring disease dynamics across cancers and other complex conditions.

systems biology↗

bioRxiv2023

State-transition Modeling of Blood Transcriptome Predicts Disease Evolution and Treatment Response in Chronic Myeloid Leukemia (CML)

Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML statespace and a three-well leukemogenic potential landscape. The potentials stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention even before phenotypic changes become detectable.

cancer biology↗

bioRxiv2023

Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), the presence of CD34 and lack of CD38 expression (CD34posCD38neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-{gamma} induces CD38 upregulation in LSC-enriched CD34posCD38neg AML blasts, but not in CD34posCD38neg HSCs. To leverage the IFN-{gamma} mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38pos blasts. Activated CD4pos and CD8pos T cells not only kill AML blasts but also produce IFN{gamma}, which leads to CD38 expression on CD34posCD38neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38neg and CD38pos AML blasts, which culminates in LSC depletion. Statement of significanceThis work represents a potential advancement in the treatment of AML, as it involves the release of IFN-{gamma} by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.

cancer biology↗

bioRxiv2019

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Daras immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

cancer biology↗