Biology subjects

Bhatia, K. S.

Publications and source records attributed to Bhatia, K. S..

3 recordsLinked to original sources

bioRxiv2025

Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

The tumor microenvironment (TME) programs cancer cells to influence therapeutic responses. Macrophages residing in TME switch from pro-phagocytic to tumor-promoting and immunosuppressive phenotypes as cancer develops. While these pro-tumor functions of macrophages are associated with poor outcomes, the underlying mechanisms by which bone-marrow (BM)-associated macrophages fuel myeloid malignancy and their precise contribution to relapse remain undissected. Here, we show expansion of monocyte/macrophage population in leukemia patients post-chemotherapy relapse, and spatial proximity of macrophages to leukemia blasts in the BM niche. This proximity proved functionally consequential--depletion of macrophages delayed leukemia relapse post cytarabine (AraC), a frontline chemotherapy, in patient-derived xenografts (PDX) and syngeneic leukemia models. Mechanistically, a pyrimidine metabolite, deoxycytidine (dC), secreted by BM macrophages, is taken up by leukemia cells to directly inhibit deoxycytidine kinase (DCK) to hamper AraC activation and subsequent resistance in a cell non-autonomous manner. Diagnosis AML patients exhibited significantly higher circulating dC levels than healthy donors, and dC levels further increased following chemotherapy. SAMHD1, which catalyzes deoxynucleoside triphosphates (dNTPs) into deoxynucleoside, was highly abundant in macrophages and mediated dC accumulation. Blockade of dC production in mouse and human macrophages via genetic and pharmacological inhibition of SAMHD1 or DHODH, a critical enzyme in pyrimidine synthesis, restored AraC sensitivity. Combination with DHODH inhibitors significantly delayed AraC relapse in human PDX and mouse syngeneic AML models. Collectively, we identify a metabolic immune-leukemia crosstalk in which SAMHD1high macrophages mediates chemoresistance by secreting pyrimidine metabolites and propose macrophage metabolic reprogramming as a tractable strategy to overcome TME-driven chemoresistance in myeloid leukemia.

cancer biology↗

bioRxiv2025

Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia

TP53 mutations across multiple cancers, including acute myeloid leukemia (AML), are associated with poor outcomes irrespective of treatment modality. However, druggable vulnerabilities beyond canonical p53 targets remain largely unexplored. We identify BIRC5 (encodes survivin), an inhibitor of the apoptosis protein (IAP) family, as a novel vulnerability in TP53 mutant AML using an unbiased, comprehensive multiomics approach -- whole-genome CRISPR knockout screen, bulk and single-cell RNA-seq, proteomics, and high-throughput drug screen. Mechanistically, BIRC5 deletion in AML restored caspase-9 and -3/7 activity and downregulated other IAPs, implicating BIRC5 as the central post-mitochondrial regulator for blocking apoptosis. p53 stabilization suppressed BIRC5 selectively in TP53 wild-type AML, explaining BIRC5 upregulation in TP53 mutant lines and AML primary tumors (n > 700). Longitudinal single-cell RNAseq (n = 22 pairs) revealed expansion of BIRC5high stem and progenitor leukemia clones in TP53 mutant AML patients post-VenAza therapy. Survivin and IAP inhibitors emerged as top combination partners with VenAza in TP53 mutant AML cells and showed potent in vivo leukemic blast inhibition in cell line and patient-derived xenograft models along with primary tumors. Beyond AML, BIRC5 was upregulated broadly across 17 of 25 TP53 mutant cancers in the TCGA cohort, and combination with survivin inhibitors overcame chemotherapy resistance in TP53 deficient triple negative breast and colorectal cancers. These findings define BIRC5 as a critical, targetable dependency and unveil survivin/IAP inhibition as a promising therapeutic axis to overcome p53-related resistance across both hematologic and solid malignancies. Key PointsO_LIBIRC5 upregulation is a novel dependency in TP53 mutant AML that mediates therapy resistance by evasion of apoptosis. C_LIO_LICombination with Survivin/IAP inhibitors overcomes venetoclax/azacitidine resistance in TP53 mutant AML. C_LI

cancer biology↗

bioRxiv2021

BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients

Early T-cell precursor (ETP) acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of T-ALL and is associated with poor survival outcomes with chemotherapy. We previously showed that maturation stage of thymocytes distinguishes pro-survival dependencies of pediatric ETP-ALL (BCL-2 dependent) from non-ETP-ALL (BCL-XL dependent). Comparable data in adults are lacking. Our present study focuses on characterizing functional dependencies of adult ETP-ALL and T-ALL on BCL-2 family proteins. Using BH3 profiling on primary tumors, we report that similar to pediatric ALL, adult ETP-ALL is primarily dependent on BCL-2; however, unlike pediatric ALL, adult non-ETP-ALL is co-dependent on both BCL-2 and BCL-XL for survival. By measuring direct mitochondrial permeabilization and cell viability assays, we validated that BH3 profiling predicted on-target cytotoxicity of venetoclax in adult ETP-ALL and navitoclax plus venetoclax in adult T-ALL. These findings provide pre-clinical evidence for venetoclax and navitoclax as potentially efficacious combination therapy for adults with T-ALL. Statement of SignificanceAdults with relapsed T-ALL have poor prognosis and represent an unmet need for novel treatments. We report that adult ETP-ALL is dependent on BCL-2 for survival, similar to pediatric ETP-ALL. However, adult non-ETP-ALL is heterogeneously dependent on both BCL-2 and BCL-XL. We characterize key dependencies on BCL-2 family proteins to direct BH3 mimetics therapy in T-ALL patients.

cancer biology↗