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The Mohi LabMohiLAB

Research · 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.

Why this matters

Transformation from a chronic blood cancer to acute myeloid leukemia is one of the worst clinical events in this disease space — survival drops sharply once it occurs. Knowing what makes one patient transform and another stay stable is the difference between watchful waiting and aggressive intervention.

The biology

AML is a genetically heterogeneous acute leukemia driven by various combinations of signaling, epigenetic, and splicing-factor mutations. Many cases evolve from preceding myeloid disorders (MPN, MDS) through stepwise acquisition of cooperating events.

The lab's earlier work in BCR/ABL- and PTPN11-driven leukemia models established a framework: a single signaling driver is rarely sufficient. Postdoctoral work demonstrated GAB2 is essential for hematopoietic transformation by BCR/ABL through both PI3K/Akt and Erk/MAPK arms, and that combining mTOR inhibitors with TKIs synergizes against BCR/ABL- and FLT3-driven leukemias, including imatinib-resistant variants. Leukemia-associated PTPN11 (Shp2) mutants were shown to be more activating than the developmental Noonan-syndrome variants and to drive a JMML-like MPN — establishing Shp2 as the first oncogenic protein tyrosine phosphatase.

More recent lab work in this theme: STAT3 activating mutations alone are insufficient to drive LGL leukemia in mice, suggesting cooperating events are required. Genetic ablation of PTPN1 (PTP1B) produces an MPN-like phenotype, suggesting PTP1B has tumor-suppressor functions in hematopoiesis. Distinct GAB2 signaling pathways drive myeloid versus lymphoid transformation in BCR-ABL1 systems.

The unifying question across these projects is the cooperating-mutation problem: which combinations of lesions push a stable clone toward acute leukemia, and which therapeutic targets exist in the transition window?

Our contribution

What the lab has shown directly, with anchors to the published papers.

  • 01

    JAK2 inhibitor monotherapy provides incomplete remission and risks AML transformation.

  • 02

    Cooperative mutations (epigenetic regulators, splicing factors) shape progression trajectory.

  • 03

    STAT3 mutations alone are insufficient to drive LGL leukemia in mice.

Open questions

What are the specific cooperating events that flip MPN or MDS into AML — and can we predict transformation early enough to intervene? The lab's current toolkit, mouse models combined with patient samples, is positioned to answer the mechanistic half of that question.

Selected publications

  1. 01

    2018British Journal of Haematology180(6):911-915

    STAT3 mutations are not sufficient to induce large granular lymphocytic leukaemia in mice

    Dutta A, Yan D, Hutchison RE, Mohi G

    PMID 28025836 ↗

  2. 02

    2017Leukemia31(5):1229-1234

    Deletion of Ptpn1 induces myeloproliferative neoplasm

    Jobe F, Patel B, Kuzmanovic T, Makishima H, Yang Y, Przychodzen B, Hutchison RE, Bence KK, Maciejewski JP, Mohi G

    PMID 28111468 ↗

  3. 03

    2016Blood127(14):1803-1813

    Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1

    Gu S, Chan WW, Mohi G, Rosenbaum J, Sayad A, Lu Z, Virtanen C, Li S, Neel BG, Van Etten RA

    PMID 26773044 ↗

  4. 04

    2005Cancer Cell7(2):179-191

    Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations

    Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, Morgan K, Boulton C, Shigematsu H, Keilhack H, Akashi K, Gilliland DG, Neel BG

    PMID 15710330 ↗

  5. 05

    2004Proceedings of the National Academy of Sciences USA101(9):3130-3135

    Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs

    Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG, Neel BG

    PMID 14976243 ↗

  6. 06

    2002Cancer Cell1(5):479-492

    Critical role for Gab2 in transformation by BCR/ABL

    Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K, Gesbert F, Iwasaki H, Li S, Van Etten RA, Gu H, Griffin JD, Neel BG

    PMID 12124177 ↗
On this theme

The full archive

The complete bibliography lives on the publications page.

All publicationsAll themesContact →

Lab page on UVA BMG: Research themes ↗ · Contact: gm7sj@virginia.edu