2-5-10 Myeloproliferative Disorders as Models of Clonal Disorders Look at cases at the end of the lecture. 1.

Discuss what is meant by a clonal hematopoietic stem cell disease. Clonality basically describes a population of daughter cells that are all derived from a single cell. In cancer the original cell is defective in some !ay often !ith some sort of genetic defect. "ince all the cells are identical clonal cells !ill all contain the e#act same defect !ithin the $tumor.% &ften times ho!ever !e don't (no! the genetic defect of the clonal tumor. In those cases !e'll loo( at surface e#pression of antigens li(e (appa)lambda ratios for multiple myeloma or CD20* in + cell lymphoma. ,e can also do -CI. analysis !hich loo(s at random inactivation of maternal - chromosomes occurring early in female embryonic development /thin( barr bodies0. 1ormal hematopoeitic cells are not clonal /myeloid and lymphoid lines produce a crapload of different cells0. 2eu(emias and lymphomas on the other hand are clonal. 3!o theories of ho! clonal stem cell diseases come about4 5nudsen 3!o 6it 6ypothesis4 t!o hits are necessary for malfunction of tumor suppressor genes /3"7s0 1o!ell 6ypothesis of Cancer 8volution4 the body does get rid of aberrant cells but at some point the body's surveillance is over!helmed and clonal proliferation occurs. 2. Describe the molecular abnormality that occurs in chronic myeloid leukemia and its role in the disease phenotype. Myeloproliferative disorders are acquired clonal hematopoietic stem cell disorders. 3hey can be chronic or acute and have variable effects on the differentiation of myeloid progenitors. 3. Understand the difference between the acute and chronic phases of the myeloproliferative neoplasms. 9cute myeloid leu(emia4 clonal leu(emia that can occur at any phase of maturation)differentiation :eactive myeloproliferations4 non-clonal disorders that are $leu(emoid% responses to drugs and infections reactive thrombocytoses from iron deficiency or chronic inflammation.

Chronic myeloid leu(emia4 CM2 is the most common myeloproliferative disease. It is caused by the t(9 22! "hiladelphia chromosome the first chromosomal abnormality that !as lin(ed to a human cancer. CM2 often presents !ith splenomegaly and leu(ocytosis. t/;<220 translocation unites 9+2 /on chromosome ;0 to +C: /on chromosome 220 to form the +cr-9bl oncogene !ith tyrosine (inase activity. =ou can locate the .hiladelphia Chromosome using #$%& /fluorescence in situ hybridi>ation0 3he identification of the .hiladelphia Chromosome has allo!ed for targeted therapy that can bloc( the tyrosine (inase activity of bcr-abl4 'leevec ($matinib!. Imatinib !or(s by binding the 93.-binding site on bcr-abl. 6o!ever gleevec alone cannot $cure% CM2 per se. 9llogenic stem cell transplant is needed to cure it. 9lthough the name CM2 implies that it's e#clusively a chronic condition it actually has both chronic and acute /blast0 phases4 3he chronic phase is a myeloproliferative phase that lasts for years and is defined by splenomegaly and leukocytosis. 6b and platelet count are usually normal. (. Distin)uish the laboratory characteristics of the myeloproliferative neoplasms (*"+s, -./ "0/ *#! from one another and from non1clonal processes. Myeloproliferative 1eoplasms /M.1s0 include4 "olycythemia (rubra! vera ("0!4 clonal hematopoietic stem cell disorder characteri>ed by elevated red cell mass)6gb. "ince you have lots of red cells EPO is usually suppressed. "plenomegaly and thrombosis /thin( rbc's clogging up both0 are the ma?or causes of morbidity. 1ote that there are other conditions that increase red cell mass such as liver or (idney tumors and cysts /resulting in high 8.&0 high altitudes /high 8.&0 testosterone therapy /high 8.&0 and high affinity hemoglobinopathies /overproduction of 8.& due to 6b that has too high affinity for o#ygen0. 9t a molecular level .@ is caused by a 2342 mutation. A952 is a tyrosine (inase that is activated by 8.& to $?ac( up% gro!th signaling. 3he mutation causes constutive upregulation of the activity of myeloid precursor cells. It's suspected that !hile ;5B of .@ patients have the A952 mutation it may not necessarily be the cause. 3hat's because leu(emic cells in .@ patients don't carry the mutation and nonspecific inhibitors of A952 don't reverse .@. 3hus it's possible that there may be an earlier mutation that incrases the chance of developing A952 abnormalities. 3he +M biopsy !ill reveal trilineage hyperplasia. In other !ords labs my reveal elevated levels of 6b 6ct and platelet /don't confuse !ith 830. 9gain 8.& !ould be lo! and A952 mutation !ould be positive. 9lso if you have a patient !ith elevated creatinine /above 1.0 for !omen 1.2 for men0 it suggests renal insufficiency !hich leads to a drop in 8.&.

"o even if 8.& levels are not given a high creatinine will raise the index of suspicion for PV. 3his !ill also help differentiate .@ from 83 since both can have elevated platelets /though 83 usually presents !ith very high platelet count0. -ssential thrombocytosis (-.!4 chronic condition of elevated platelet counts Must rule out inflammatory disorders malignancy and iron deficiency ,ill see clusters of megs in a +M biopsy 50B patients have a 2342 or c*"L mutation Main complication is thrombosis 2o! rate of transformation to myelofibrosis or acute leu(emia /10B0< patients can live for very long unli(e in MC. 9lso if you see someone !ith *yelofibrosis (*#!4 patients present !ith hepatosplenomegaly and progressive anemia. 3here is fibrosis of the bone marro!. .atients become transfusion-dependent and have shortened life span in contrast to 8@ and .@ D0-50B have the 2342 mutation 9llogeneic stem cell transplant is a potential cure but there's high mortality and morbidity &n .+ smear MC has characteristic tear-drop red blood cells as !ell as nucleated red cells and early myeloid cells. MC comes out positive for Reticulin tain !hich visuali>es fibrosis in the +M. 5hronic myelomonocytic Leukemia (5**L!4 a condition of monocytosis that's no! considered an overlap syndrome !ith features of both myelodysplastic syndromes /MD"0 and myeloproliferative neoplasms /M.10. 8#4 patient presents !ith appendicitis and gets very high platelet counts. !on"t confuse this with E#. 8":)C:. measure inflammation. If this tests negative and platelets are high then loo( at the other myeloproliferative syndromes.