Research · The Mohi Lab
Six fronts.
One signaling network.
We work at the molecular pathogenesis of blood cancer, with a single throughline: find what to target next. Three clusters of biology connect the work. The JAK / STAT axis where one mutation (JAK2V617F) drives three distinct MPNs. The splicing-factor cluster where U2AF1 and SRSF2 errors collapse hematopoiesis in MDS. The inflammation arm where chronic IL-1 signaling cooperates with these genetic lesions to push disease forward. Each front below is a working hypothesis backed by a mouse model and, when the biology warrants it, a clinical trial.
01 · JAK2V617F · MPN
How a single mutation drives three blood cancers.
Polycythemia vera, essential thrombocythemia, myelofibrosis.
The same JAK2V617F mutation produces three distinct myeloproliferative neoplasms. We use inducible knock-in mouse models to ask why dose, cell-of-origin, and cooperating mutations decide the disease that emerges.
- Heterozygous JAK2V617F drives PV; homozygous expression accelerates progression to myelofibrosis.
- STAT5 deletion completely blocks JAK2V617F-induced PV; STAT3 is dispensable.
- Loss of EZH2 cooperates with JAK2V617F to promote myelofibrosis.
- HMGA2 sits downstream of EZH2 and drives MF through TGF-β1 and CXCL12.
- Targets
- JAK2 · STAT5 · STAT3 · EZH2 · HMGA2 · TGF-β1 · CXCL12
- Drugs
- Ruxolitinib
- Models
- JAK2V617F knock-in mouse · MPLW515L
Read theme essay
02 · IL-1 · Inflammation
Chronic inflammation as a driver of clonal expansion.
Targeting the IL-1 axis in MPN.
JAK inhibitors manage MPN symptoms but don't reverse fibrosis or eliminate the mutant clone. We identified IL-1 signaling as a key driver of clonal expansion and bone marrow fibrosis, and showed that IL-1R1 antibody blockade reduces disease burden in murine MPN.
- IL-1 signaling drives clonal expansion of JAK2V617F-mutant cells.
- IL-1R1 antibody blockade reduces bone marrow fibrosis in murine MPN.
- IL-1 inhibition complements JAK2 inhibition mechanistically.
- Targets
- IL-1 · IL-1R1 · JAK2
- Models
- JAK2V617F knock-in mouse
Read theme essay
03 · PIM kinases · Bench to clinic
PIM1 inhibition: from a mouse model to a Phase 1/2 trial.
TP-3654, now Nuvisertib.
PIM1 expression is markedly elevated in MPN progenitors. Genetic ablation blocks myelofibrosis; the small-molecule PIM1 inhibitor TP-3654 ameliorates disease in mice. The work led directly to a multicenter clinical trial, with UVA Cancer Center as a major site.
- PIM1 expression elevated in MPN progenitors; genetic ablation prevents myelofibrosis.
- TP-3654 reduces leukocytosis, splenomegaly, and bone marrow fibrosis in murine MPN.
- TP-3654 inhibits mTORC1, MYC, and TGF-β signaling and reduces collagen output.
- Combined TP-3654 + Ruxolitinib normalizes blood counts and abrogates marrow fibrosis.
- Targets
- PIM1 · CDK6 · mTORC1 · MYC · TGF-β
- Drugs
- TP-3654 (Nuvisertib) · Palbociclib · Ruxolitinib
- Models
- JAK2V617F · MPLW515L
- Trial
- NCT04176198 ↗
Read theme essay
04 · U2AF1 · MDS
When splicing fails, hematopoiesis collapses.
Splicing-factor mutations as MDS drivers.
U2AF1 mutations are found in ~11% of MDS cases. We use conditional knockout and knock-in alleles to dissect how this single splicing-factor lesion produces stem-cell failure, replication stress, and the dysplastic phenotype.
- U2AF1 deletion produces pancytopenia, HSPC loss, bone marrow failure, and early lethality.
- U2AF1 is required for HSC maintenance, repopulation, and progenitor survival.
- U2AF1-Q157R knock-in mice develop macrocytic anemia, erythroid dysplasia, and HSC expansion.
- Likely mechanism: aberrant splicing → gene expression changes + DNA damage + replication stress.
- Targets
- U2AF1 · SRSF2 · SF3B1
- Models
- Conditional U2AF1 knockout · U2AF1-Q157R knock-in
Read theme essay
05 · AML · Progression
Mechanisms of AML evolution and therapy resistance.
What pushes MPN and MDS toward acute leukemia.
JAK inhibitors reduce symptoms but don't cure; some patients progress to acute myeloid leukemia. We study the cooperating mutations and signaling rewires that license MPN/MDS to transform into AML, and what therapeutic windows exist before that transition.
- JAK2 inhibitor monotherapy provides incomplete remission and risks AML transformation.
- Cooperative mutations (epigenetic regulators, splicing factors) shape progression trajectory.
- STAT3 mutations alone are insufficient to drive LGL leukemia in mice.
- Targets
- BCR/ABL · PTPN11/Shp2 · STAT3 · GAB2
- Drugs
- Imatinib · Rapamycin
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06 · TNBC · Solid tumor
PIM kinases in triple-negative breast cancer.
Extending the PIM hypothesis beyond hematologic malignancy.
Triple-negative breast cancer is the most aggressive breast subtype: metastasis drives mortality, chemotherapy resistance is common. PIM1 and PIM2 are markedly overexpressed in TNBC. We're testing whether the same PIM-inhibitor strategy that worked in myelofibrosis can be repurposed.
- PIM1 and PIM2 elevated in TNBC tumors.
- PIM1/PIM2 deletion blocks tumor growth and metastasis in MMTV-PyMT mice.
- TP-3654 reduces TNBC cell growth, overcomes chemotherapy resistance in vitro.
- In vivo, TP-3654 markedly inhibits primary tumor growth and metastasis.
- Targets
- PIM1 · PIM2
- Drugs
- TP-3654 · docetaxel · doxorubicin · carboplatin
- Models
- MMTV-PyMT transgenic
Read theme essay
The lab’s biology,
as one map.
The published work, drawn as a single signaling diagram. Click a node to read what role it plays and where the lab has put pressure on it.
Click a node to read its role & mechanism. Tap again to deselect.
From a working hypothesis to a clinical trial.