A role for Heme in Driving Venetoclax Resistance in Multiple Myeloma (MM)

Multiple myeloma (MM) is cancer of plasma cells, a type of white blood cell found in the bone marrow, affecting about 36,000 new cases and resulting in approximately 10, 850 deaths per year, according to the American Cancer Society.¹  Current treatment involves a combination of several drugs to promote cancer cell apoptosis and prevent them from growing and multiplying. Venetoclax (Ven), a BCL‑2 inhibitor, is an effective therapy in selected subsets of MM, particularly patients diagnosed with the t(11;14) translocation or tumors with low mitochondrial electron transport chain (ETC) activity.

This study highlighted in Blood, shows that diminished ETC function lowers the apoptotic threshold, sensitizing MM cells to venetoclax and investigates how the metabolism of heme modulates this sensitivity.

The Spotlight

Keywords: Cancer cells, metabolism, multiple myeloma, apoptosis, heme, purine, biosynthesis

Experiment purpose: Ven sensitive KMS12PE cells with or without hemin, were cultured in RPMI 1640, without l-glutamine, without glucose, and 10% Dialyzed FBS, to precisely control metabolic inputs. Then underwent stable isotope tracing, labelled  with (amide-¹⁵N) glutamine or (¹⁵N₄) hypoxanthine isotopes to dissect heme-dependent resistance mechanisms, specifically de novo versus salvage purine biosynthesis pathways.

Product highlights:

RPMI 1640, no Glucose, no L-glutamine
RPMI Medium 1640 has been specifically developed for the long-term culture of blood cells, the culture of normal and abnormal human leukocytes (e.g. neoplastic WBC’s) and is now used as a general medium (with serum) for hybridoma cultures.  This spotlight highlights the use of Captivate Bio’s cell culture media.

References: Nair R. et al. (2025) Heme promotes venetoclax resistance in multiple myeloma through MEK‑ERK signaling and purine biosynthesis. Blood 145(7):732–747 (2025).

Commentary article: Fulciniti, M. (2025) Heme fuels venetoclax resistance in multiple myeloma Blood (2025) 145 (7): 658–660.

Data

Figure: Heme supplementation increases purine synthesis. Stick figures showing incorporation of labeled glutamine (G) and hypoxanthine (L). Fractional enrichment of KMS12PE cells treated with or without hemin and labeled with glutamine (H-K) and hypoxanthine (M-P). Indicated VS cell lines KMS12PE and OCIMY5 pretreated with mycophenolic acid (MPA) (Q), purine biosynthesis inhibitor, and brequinar (BREQ) (R), pyrimidine biosynthesis inhibitor, for 30 minutes followed by treatment with ±50 μM hemin and 0.05 μM Ven. For panels Q, and R, cell death/viability evaluated by annexin V/DAPI flow cytometric staining, n = 3. P value is calculated using the 2-way analysis of variance (ANOVA). ∗P = .01 to .05, ∗∗P = .001 to .1, ∗∗∗P = .0001 to .001, and ∗∗∗∗P < .0001. ns, not significant.

Conclusion

The ¹⁵N-glutamine following the de novo pathway revealed an increase in purine synthesis, while the  (¹⁵N₄) hypoxanthine produced a decrease in purine synthesis in the salvage pathway, indicating that heme promotes venetoclax resistance through de novo purine synthesis.

Treatment of these cells with mycophenolic acid, a purine biosynthesis inhibitor, significantly reversed heme-induced resistance, signifying that disrupting heme metabolism or combining apoptotic pathway inhibitors can overcome this resistance, offering new strategies for treating multiple myeloma.