Transcript 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
• 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!
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 Hoxa9
and Meis1
Nakamura et al. (1996)
Hoxa9 and Meis1 are normally active during
Hematopoesis
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)
Hematopoesis: Hoxa9 & Meis1 are normally
downregulated during differentiation into Mature Cells
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!
Altered Hoxa9 and Meis1 into oncogenes results in
presence during, and shutting off of, differentiation!
Result? Vast increase in numbers of premature myeloid
cells -> called blast cells
If the world was taken over…by precocious teenagers
Overproliferated blast cells take over, resulting in the
malignancy Acute Myeloid Leukemia
Normal
Heterogeneous mixture of myeloid
and erythroid cells
AML
Increased numbers of blasts (note
prominent Golgi area in cytoplasm of
blasts)
Pathophysiology of AML
•Most common complaints are fatigue, malaise, and a profound weakness
worsening over 2-3 months- this is bone marrow failure:
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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].
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•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.
Expression of AML
Worst Case Expression of AML (not treated in time)
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
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)