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The Story of HOXA9 and AML

The Story of HOXA9 and AML. Nisarg Desai. HOXA9 is a Homeobox (HB) Gene: HB genes are highly conserved. Mouse Hoxa9 homolog of human HOXA9 : Makes mouse models very effective. The discovery of Hoxa9’s role as a proto-oncogene in leukemias.

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The Story of HOXA9 and AML

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  1. The Story of HOXA9 and AML Nisarg Desai

  2. HOXA9 is a Homeobox (HB) Gene: HB genes are highly conserved

  3. Mouse Hoxa9 homolog of human HOXA9: Makes mouse models very effective

  4. The discovery of Hoxa9’s role as a proto-oncogene in leukemias • 80’s – Scientists discover overexpression of Hoxb8 in leukemias and lymphomas • Method: Retroviral insertions & Proviral Tagging • Early 90’s – Discover role of other Hox and non-Hox genes in leuks. and lymphs. • Nakamura et al. (1996) -> Discover cooperative activation of Hoxa9 and Meis1!

  5. Nakamura et al. (1996) use Chromosome Walking and Southern blot analysis to find… • Consistent cosegregation: Known proviral sequence from BXH-2 strain leukemias w/ Hoxa9 sequence! • Viral integration of sequence (Evi6) -> High level Hoxa9 protein expression • Meis1 -> already shown to be a common integration site in BXH-2 tumors • 95% of viral integrations -> Increased expression of Hoxa9andMeis1 Nakamura et al. (1996)

  6. Pluripotent Stem Cell (PPSC)   this original cell can move in 2 directions lymphoid stem cell myeloid stem cell •   • All lymphocytes All other blood cells • (RBC, WBC, and platelets) Hoxa9 and Meis1 are normally active during Hematopoesis

  7. Hematopoesis: Hoxa9 & Meis1 are normally downregulated during differentiation into Mature Cells

  8. So how does Hoxa9 (and thus HOXA9 in humans) and Meis1 proteins normally function? • MEIS is family of cofactor proteins • Functionally related to PBX family • PBX family have shown to strongly modulate Hox protein binding to DNA • Thus, Meis1 is a modulator of Hoxa9 protein binding to DNA -> together, transcriptionally enhance/repress downstream genes!

  9. Altered Hoxa9 and Meis1 into oncogenes results in presence during, and shutting off of, differentiation!

  10. Result? Vast increase in numbers of premature myeloid cells -> called blast cells If the world was taken over…by precocious teenagers

  11. Overproliferated blast cells take over, resulting in the malignancy Acute Myeloid Leukemia Normal AML Increased numbers of blasts (note prominent Golgi area in cytoplasm of blasts) Heterogeneous mixture of myeloid and erythroid cells

  12. Pathophysiology of AML •Most common complaints are fatigue, malaise, and a profound weakness worsening over 2-3 months- this is bone marrow failure: • Hypermetabolic symptoms (Fatigue, sweats, weight loss) • Anemia (Fatigue, dyspnea) • Neutropenia (Opportunistic infections) • Thrombocytopenia (Ecchymoses, petechiae, mucocutaneous bleeding) • Hyperleukocytosis [Mental status changes (somnolence), Dyspnea with bilateral infiltrates on chest x-ray]. • •Acute leukemias cause morbidity/mortality 3 ways: • --deficiency in normal blood cell or function; • --invasion of vital organs with impairment of function; • --systemic disturbances shown by metabolic imbalance.

  13. Expression of AML

  14. Worst Case Expression of AML (not treated in time)

  15. Some AML Patients show t(7;11)(p15;p15), where nucleoporin gene NUP98 is fused to HOXA9 • Nucleoporins are constituent building blocks of nuclear pores • Invariant chimeric protein may be able to control its own entry into nucleus, thereby bypassing regulatory mechanisms -> Hoxa9 proteins become constitutively active

  16. What about rest of patients? • Exact mechanisms are under investigation, but will take time to elucidate b/c HOXA9 protein has major activation and/or repression effects on currently known 220 downstream genes! Dorsam et al. (2004)

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